Substituted Morphinans and the Use Thereof

ABSTRACT

The application is directed to compounds of Formula I: 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts and solvates thereof, wherein R 1 , R 2 , R 3 , R 4a , and R 4b  are defined as set forth in the specification. The invention is also directed to use of compounds of Formula I to treat disorders responsive to the modulation of one or more opioid receptors, or as synthetic intermediates. Certain compounds of the present invention are especially useful for treating pain.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This application is in the field of medicinal chemistry. The applicationrelates to novel substituted morphinan derivatives, pharmaceuticalcompositions comprising any of these compounds, and their use.

2. Description of the Related Art

Pain is the most common symptom for which patients seek medical adviceand treatment. While acute pain is usually self-limited, chronic paincan persist for 3 months or longer and lead to significant changes in apatient's personality, lifestyle, functional ability and overall qualityof life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100-107, J. C.Bennett and F. Plum eds., 20th ed. 1996).

Pain has traditionally been managed by administering either a non-opioidanalgesic (such as acetylsalicylic acid, choline magnesiumtrisalicylate, acetaminophen, ibuprofen, fenoprofen, diflunisal ornaproxen), or an opioid analgesic (such as morphine, hydromorphone,methadone, levorphanol, fentanyl, oxycodone, oxymorphone, orbuprenorphine).

Until recently, there was evidence of three major classes of opioidreceptors in the central nervous system (CNS), with each class havingsubtype receptors. These receptor classes are known as μ, δ, and κ. Asopiates have a high affinity to these receptors while not beingendogenous to the body, research followed in order to identify andisolate the endogenous ligands to these receptors. These ligands wereidentified as endorphins, enkephalins, and dynorphins, respectively.Additional experimentation has led to the identification of the opioidreceptor-like (ORL-1) receptor, which has a high degree of homology tothe known opioid receptor classes. This more recently discoveredreceptor was classified as an opioid receptor based only on structuralgrounds, as the receptor did not exhibit pharmacological homology. Itwas initially demonstrated that non-selective ligands having a highaffinity for μ, δ, and κ receptors had low affinity for the ORL-1receptor. This characteristic, along with the fact that an endogenousligand had not yet been discovered, led to the ORL-1 receptor beingdesignated as an “orphan receptor”.

Kappa (κ) opioid receptor agonists have been evaluated as alternativesto existing analgesics for the treatment of pain. Centrally penetratingκ agonists produce antinociceptive effects in conventional preclinicalassays of basal, inflammatory and neuropathic pain (Vanderah el al., J.Pharmacol. Exp. Ther. 310:326-333 (2004); Negus et al.,Psychopharmacology (Berl) 210:149-159 (2010)). However, centrallypenetrating κ agonists also produce undesirable side-effects, such assedative and psychotomimetic effects (Pande et al., Clin.Neuropharmacol. 19:92-97 (1996); Pande el al., Clin. Neuropharmacol.19:451-456 (1996); and Wadenberg, CNS Drug Rev. 9:187-198 (2003)).

Opioid receptor agonists that do not readily cross the blood-brainbarrier are peripherically restricted and distribute poorly to thecentral nervous system after systemic administration. Such compoundswould retain an ability to produce analgesia by acting on peripheralopioid receptors, such as peripheral κ-opioid receptors, but theirpotency to produce centrally mediated side-effects would be reduced.

There is a need for effective analgesics that work by acting on opioidreceptors. There is also a need for analgesics that work by acting onperipheral opioid receptors. There is also a need for analgesics thatwork by acting on central opioid receptors. There is also a need foranalgesics that work by acting on κ-opioid receptors. There is also aneed for analgesics that work by acting on peripheral κ-opioidreceptors.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides compounds represented byFormulae I-XIII, I-A-XIII-A, and XIV-XVI, below, and thepharmaceutically acceptable salts and solvates thereof, collectivelyreferred to herein as “Compounds of the Invention” (each is individuallyreferred to hereinafter as a “Compound of the Invention”).

In another aspect, the present disclosure provides Compounds of theInvention for use as synthetic intermediates.

In another aspect, the present disclosure provides the use of Compoundsof the Invention as modulators of one or more opioid receptors.Specifically, the present disclosure provides the use of Compounds ofthe Invention as modulators of μ, δ, κ, and/or ORL-1 opioid receptors,and especially modulators of μ and/or κ opioid receptors.

In another aspect, the present disclosure provides a method of treatingor preventing a disorder responsive to the modulation of one or moreopioid receptors in a patient, comprising administering to the patientan effective amount of a Compound of the Invention.

In another aspect, the present disclosure provides a use of a Compoundof the Invention as an analgesic to treat or prevent pain; or as anagent to treat or prevent withdrawal from alcohol or drug addiction; oras an agent to treat or prevent addictive disorders; or as an agent totreat a pruritic condition; or as an agent to treat or preventconstipation; or as an agent to treat or prevent diarrhea (each of pain,alcohol withdrawal, drug withdrawal, addictive disorders, pruritis,constipation, and diarrhea being a “Condition”).

The present invention further provides methods of treating or preventinga Condition, comprising administering to a patient in need thereof atherapeutically effective amount of a Compound of the Invention. Incertain embodiments, the Condition is pair (including acute pain,chronic pain (which includes but is not limited to, neuropathic pain,postoperative pain, and inflammatory pain), and surgical pain). TheCompounds of the Invention are particularly useful for treating orpreventing chronic pain.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a Compoundof the Invention and one or more pharmaceutically acceptable carriers.Such compositions are useful for treating or preventing a Condition in apatient.

In another aspect, the present disclosure provides Compounds of theInvention for use in treatment or prevention of a disorder responsive tothe modulation of one or more opioid receptors. Preferably, the disorderis responsive to modulation of the μ-opioid receptor or the κ-opioidreceptor, or to modulation of a combination thereof.

In another aspect, the present disclosure provides a method ofmodulating one or more opioid receptors in a patient in need of saidmodulation, comprising administering to the patient an opioid receptormodulating amount of a Compound of the Invention.

In another aspect, the present disclosure provides Compounds of theInvention for use in treatment or prevention of one or more Conditionsin a patient in need of said treatment or prevention.

In another aspect, the present disclosure provides Compounds of theInvention for use in treatment or prevention of pain in a patient, suchas acute pain, chronic pain (which includes but is not limited to,neuropathic pain, postoperative pain, and inflammatory pain), orsurgical pain surgical.

In another aspect, the present disclosure provides Compounds of theInvention for use in modulation of one or more opioid receptors in apatient.

In another aspect, the present disclosure provides use of Compounds ofthe Invention in the manufacture of a medicament for treating orpreventing a disorder responsive to the modulation of one or more opioidreceptors.

In another aspect, the present disclosure provides use of Compounds ofthe invention in the manufacture of a medicament for modulating of oneor more opioid receptors in a patient. Preferably, the μ- or κ-opioidreceptor is modulated, or both the μ- and κ-receptors are modulated.

In another aspect, the present disclosure provides Compounds of theInvention for use as a medicament.

In another aspect, the present disclosure provides use of a Compound ofthe Invention in the manufacture of a medicament for treating orpreventing a Condition in a patient.

In another aspect, the present disclosure provides use of a Compound ofthe Invention in the manufacture of a medicament for treating orpreventing pain in a patient, such as acute pain, chronic pain, orsurgical pain.

In another aspect, the present disclosure provides a pharmaceuticalcomposition, comprising a Compound of the Invention for treating orpreventing a disorder responsive to the modulation of one or more opioidreceptors.

The present invention further provides methods for preparing apharmaceutical composition, comprising admixing a Compound of theInvention and a pharmaceutically acceptable carrier to form thepharmaceutical composition.

In another aspect, the present invention provides radiolabeled Compoundsof the Invention, especially ¹H, ¹¹C, and ¹⁴C radiolabeled Compounds ofthe Invention, and the use of such compounds as radioligands to detectbinding to an opioid receptor in screening assays.

In another aspect, the present invention provides a method for screeninga candidate compound for the ability to bind to an opioid receptor,comprising a) introducing a fixed concentration of a radiolabeledCompound of the Invention to the receptor under conditions that permitbinding of the radiolabeled compound to the receptor to form a complex;b) titrating the complex with a candidate compound; and c) determiningthe binding of the candidate compound to said receptor.

In a further aspect, the invention relates to a kit, comprising asterile container containing an effective amount of a Compound of theInvention and instructions for therapeutic use.

Additional embodiments and advantages of the disclosure will be setforth, in part, in the description that follows, and will flow from thedescription, or can be learned by practice of the disclosure. Theembodiments and advantages of the disclosure will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only, and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

Certain Compounds of the Invention are useful for modulating apharmacodynamic response from one or more opioid receptors, e.g., μ, δ,κ, or ORL-1, either centrally or peripherally, or both. Thepharmacodynamic response may be attributed to the compound eitherstimulating (agonizing) or inhibiting (antagonizing) the one or morereceptors. Certain Compounds of the Invention may antagonize one or moreopioid receptors, and also agonize one or more other receptors.Compounds of the Invention having agonist activity may be either full orpartial agonists. Certain Compounds of the Invention are also useful assynthesis intermediates.

In one embodiment, Compounds of the Invention are compounds representedby Formula I-A:

and the pharmaceutically acceptable salts and solvates thereof, wherein:

R¹ is hydrogen, OH, halo, cyano, carboxy, or aminocarbonyl; or alkyl,alkenyl, alkynyl, alkoxy, alkenyloxy, or alkynyloxy, any of which isoptionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, halo, haloalkyl, amino,alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionallysubstituted with 1, 2, or 3 independently selected R^(11a) groups; or—O—PG, wherein PG is a hydroxyl protecting group;

-   -   R² is:    -   (a) hydrogen or carboxamido; or    -   (b) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl,        (cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl,        heteroarylalkyl, alkylcarbonyl, alkoxycarbonyl,        (arylalkoxy)carbonyl, or (heteroarylalkoxy)carbonyl, any of        which is optionally substituted with 1, 2, or 3 substituents,        each independently selected from the group consisting of        hydroxy, alkyl, halo, haloalkyl, amino, alkylamino,        dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,        heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl,        heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are        optionally substituted with 1, 2, or 3 independently selected        R^(11a) groups;    -   R³ is hydrogen, OH, or halo; or alkoxy, alkylamino, or        dialkylamino, any of which is optionally substituted with 1, 2,        or 3 substituents, each independently selected from the group        consisting of hydroxyl, halo, haloalkyl, amino, alkylamino,        dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,        heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl,        heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are        optionally substituted with 1, 2, or 3 independently selected        R^(11a) groups;    -   R^(4a1) is selected from the group consisting of C₃-C₆ alkyl,        arylalkyl, (cycloalkyl)alkyl, C₃-C₆ alkoxy, aralkyloxy,        —N(H)COR^(4c), —CH₂C(═O)NR^(4d)R^(4e), and —N(H)SO₂R^(4f),

-   -   R^(4b1) is selected from the group consisting of hydrogen and        R^(4a)-I; or    -   R^(4a1) and R^(4b1) taken together form an alkenyl; e.g.,        ═C(H)CH₃CH(CH₃);    -   R^(4c) is alkyl, cycloalkyl, heterocyclo, arylalkyl, or aryl,        any of which is optionally substituted with 1, 2, or 3        substituents, each independently selected from the group        consisting of hydroxy, alkyl, halo, haloalkyl, amino,        alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,        heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein        the aryl and cycloalkyl are optionally substituted with 1, 2, or        3 independently selected R^(11a) groups;    -   R^(4d) is hydrogen; or alkyl, cycloalkyl, arylalkyl, or aryl,        any of which is optionally substituted with 1, 2, or 3        substituents, each independently selected from the group        consisting of hydroxy, alkyl, halo, haloalkyl, amino,        alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,        heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein        the aryl, heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl        are optionally substituted with 1, 2, or 3 independently        selected R^(11a) groups;    -   R^(4e) is hydrogen; or alkyl, optionally substituted with 1, 2,        or 3 substituents, each independently selected from the group        consisting of hydroxy, alkyl, halo, haloalkyl, amino,        alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,        heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl; or    -   R^(4d) and R^(4e) taken together with the nitrogen atom to which        they are attached form a 4- to 8-membered heterocyclo, wherein        the heterocyclo is optionally substituted with 1 or 2        substituents, each independently selected from the group        consisting of alkyl, hydroxy, halo, haloalkyl, amino,        alkylamino, dialkylamino, alkoxy, aminocarbonyl, arylalkyl, and        aryl, wherein the alkyl, arylalkyl, and aryl are optionally        substituted with 1, 2, or 3 independently selected R^(11a)        groups;    -   R^(4f) is alkyl, cycloalkyl, arylalkyl, or aryl, any of which is        optionally substituted with 1, 2, or 3 substituents, each        independently selected from the group consisting of hydroxy,        alkyl, halo, haloalkyl, amino, alkylamino, dialkylamino,        carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo,        cycloalkyl, and cycloalkenyl, wherein the aryl and cycloalkyl        are optionally substituted with 1, 2, or 3 independently        selected R^(11a) groups;    -   each R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), and R^(5f) is        independently selected from the group consisting of hydrogen and        alkyl;    -   R⁶ is hydrogen or alkyl;    -   R⁷ is hydrogen or alkyl;    -   R^(8a) is hydrogen, or alkyl, cycloalkyl, cycloalkenyl,        heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl,        (cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl, or        heteroarylalkyl, any of which is optionally substituted with 1,        2, or 3 substituents, each independently selected from the group        consisting of hydroxy, alkyl, halo, haloalkyl, amino,        alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,        heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein        the aryl, heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl        are optionally substituted with 1, 2, or 3 independently        selected R^(11a) groups;    -   R^(8b) is hydrogen or alkyl, wherein the alkyl is optionally        substituted with 1, 2, or 3 substituents, each independently        selected from the group consisting of alkyl, hydroxy, halo,        haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,        alkoxycarbonyl, and aminocarbonyl; or    -   R^(8a) and R^(8b) taken together with the carbon atom to which        they are attached form a 3- to 8-membered cycloalkyl; or    -   R⁷ and R^(8a) taken together with the atoms to which they are        attached form a 4- to 8-membered heterocyclo, wherein the        heterocyclo is optionally substituted with 1 or 2 substituents,        each independently selected from the group consisting of alkyl,        hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino,        carboxy, alkoxy, alkoxycarbonyl, and aminocarbonyl;    -   R⁹ is hydrogen or alkyl;    -   R¹⁰ is hydrogen, or alkyl, cycloalkyl, cycloalkenyl,        heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl,        (cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl, or        heteroarylalkyl, any of which is optionally substituted with 1,        2, or 3 substituents, each independently selected from the group        consisting of hydroxy, alkyl, halo, haloalkyl, amino,        alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,        heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein        the aryl, heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl        are optionally substituted with 1, 2, or 3 independently        selected R^(11a) groups;    -   each R^(11a) is independently selected from the group consisting        of hydroxy, halo, alkyl, haloalkyl, cyano, nitro, amino,        alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl;    -   n is 1, 2, or 3;    -   o is 1, 2, or 3; and    -   p is 1, 2, or 3.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula I:

and the pharmaceutically acceptable salts and solvates thereof, wherein:

R¹ is hydrogen, OH, halo, cyano, carboxy, or aminocarbonyl; or alkyl,alkenyl, alkynyl, alkoxy, alkenyloxy, or alkynyloxy, any of which isoptionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, halo, haloalkyl, amino,alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups; or —O—PG,wherein PG is a hydroxyl protecting group;

R² is:

-   -   (a) hydrogen or carboxamido; or    -   (b) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl,        (cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl,        heteroarylalkyl, alkylcarbonyl, alkoxycarbonyl,        (arylalkoxy)carbonyl, or (heteroarylalkoxy)carbonyl, any of        which is optionally substituted with 1, 2, or 3 substituents,        each independently selected from the group consisting of        hydroxy, alkyl, halo, haloalkyl, amino, alkylamino,        dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,        heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl,        heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are        optionally substituted with 1, 2, of 3 independently selected        R¹¹ groups;

R³ is hydrogen, OH, or halo; or alkoxy, alkylamino, or dialkylamino, anyof which is optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxyl, halo,haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein the aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl are optionally substituted with 1, 2, or 3 independentlyselected R¹¹ groups;

R^(4a) is selected from the group consisting of:

R^(4b) is selected from the group consisting of hydrogen and R^(4a)-I;

each R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), and R^(5f) is independentlyselected from the group consisting of hydrogen and alkyl;

R⁶ is hydrogen or alkyl;

R⁷ is hydrogen or alkyl;

R^(8a) is hydrogen, or alkyl, cycloalkyl, cycloalkenyl, heterocyclo,aryl, heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl,(heterocyclo)alkyl, arylalkyl, or heteroarylalkyl, any of which isoptionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, alkyl, halo, haloalkyl,amino, alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups;

R^(8b) is hydrogen or alkyl, wherein the alkyl is optionally substitutedwith 1, 2, or 3 substituents, each independently selected from the groupconsisting of alkyl, hydroxy, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, and aminocarbonyl; or

R^(8a) and R^(8b) taken together with the carbon atom to which they areattached form a 3- to 8-membered cycloalkyl; or

R⁷ and R^(8a) taken together with the atoms to which they are attachedform a 4- to 8-membered heterocyclo, wherein the heterocyclo isoptionally substituted with 1 or 2 substituents, each independentlyselected from the group consisting of alkyl, hydroxy, halo, haloalkyl,amino, alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, andaminocarbonyl;

R⁹ is hydrogen or alkyl;

R¹⁰ is hydrogen, or alkyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl,heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (heterocyclo)alkyl,arylalkyl, or heteroarylalkyl, any of which is optionally substitutedwith 1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, alkyl, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl are optionally substitutedwith 1, 2, or 3 independently selected R¹¹ groups;

each R¹¹ is independently selected from the group consisting of hydroxy,halo, alkyl, haloalkyl, nitro, amino, alkylamino, dialkylamino, carboxy,alkoxy, and alkoxycarbonyl;

-   -   n is 1, 2, or 3;    -   o is 1, 2, or 3; and    -   p is 1, 2, or 3.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula II-A:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a1) and R^(4b1) are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula II:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a), and R^(4b) are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula III-A:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R₃, R^(4a1), and R^(4b1) are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula III:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a), and R^(4b) are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula IV-A:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a1), and R^(4b1) are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula IV:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a1), and R^(4b1) are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula V-A:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a1), and R^(4b1) are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula V:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a), and R^(4b) are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula VI-A:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a1), and R^(4b1) are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the invention are compoundsrepresented by formula VI:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a), and R^(4b) are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula VII-A:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a1), and R^(4b1) are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula VII:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a), and R^(4b) are as defined above in connection withFormula.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula VIII-A:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a1), and R^(4b1) are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula VIII:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a), and R^(4b) are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula IX-A:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R₃, R^(4a1) and R^(4b1) are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula IX:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a), and R^(4b) are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula X-A:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a1), and R^(4b1) are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula X:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a), and R^(4b) are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula XI-A:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a1), and R^(4b1) are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula XI:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a), and R^(4b) are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula XII-A:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a1), and R^(4b1) are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula XII:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a), and R^(4b) are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula XIII-A:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a1), and R^(4b1) are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula XIII:

and the pharmaceutically acceptable salts and solvates thereof, whereinR¹, R², R³, R^(4a), and R^(4b) are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formula I-A, II-A, III-A, IV-A, V-A, VI-A,VII-A, VIII-A, IX-A, X-A, XI-A, XII-A, or XIII-A (referred tocollectively as “Formulae I-A-XIII-A”), and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4b1) is hydrogen, andR¹, R², R³, and R^(4a1) are as defined above in connection with FormulaI-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof; wherein R^(4b) is hydrogen, andR¹, R², R³, and R^(4a) are as defined above in connection with FormulaI.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R¹ is hydrogen, OH, halo,cyano, carboxy, or aminocarbonyl; or alkyl, alkenyl, alkynyl, alkoxy,alkenyloxy, or alkynyloxy, any of which is optionally substituted with1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino,carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo,cycloalkyl, and cycloalkenyl, wherein the aryl, heteroaryl, heterocyclo,cycloalkyl, and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R^(11a) groups, and R², R³, R^(4a1), R^(4b1), andR^(11a) are as defined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R¹ is hydrogen, OH, halo,cyano, carboxy, or aminocarbonyl; or alkyl, alkenyl, alkynyl, alkoxy,alkenyloxy, or alkynyloxy, any of which is optionally substituted with1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino,carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo,cycloalkyl, and cycloalkenyl, wherein the aryl, heteroaryl, heterocyclo,cycloalkyl, and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R¹¹ groups, and R², R³, R^(4a), R^(4b), and R¹¹are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R¹ is OH or unsubstitutedC₁₋₆ alkoxy, e.g., —OCH₃, and R², R³, R^(4a1), and R^(4b1) are asdefined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R¹ is OH or unsubstitutedC₁₋₆ alkoxy, e.g., —OCH₃, and R², R³, R^(4a), and R^(4b) are as definedabove in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R² is hydrogen orcarboxamido, and R¹, R³, R^(4a1), and R^(4b1) are as defined above inconnection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R² is hydrogen orcarboxamido, and R¹, R³, R^(4a), and R^(4b) are as defined above inconnection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R² is alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl,(cycloalkyl)alkyl, (cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl,heteroarylalkyl, alkylcarbonyl, alkoxycarbonyl, (arylalkoxy)carbonyl, or(heteroarylalkoxy)carbonyl, any of which is optionally substituted with1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, alkyl, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl are optionally substitutedwith 1, 2, or 3 independently selected R^(11a) groups, and R¹, R³,R^(4a1), R^(4b1), and R^(11a) are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R² is alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl,(cycloalkyl)alkyl, (cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl,heteroarylalkyl, alkylcarbonyl, alkoxycarbonyl, (arylalkoxy)carbonyl, or(heteroarylalkoxy)carbonyl, any of which is optionally substituted with1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino,carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo,cycloalkyl, and cycloalkenyl, wherein the aryl, heteroaryl, heterocyclo,cycloalkyl, and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R¹¹ groups, and R¹, R³, R^(4a), R^(4b), and R¹¹are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R² is C₃₋₇(cycloalkyl)(C₁₋₄)alkyl or C₃₋₇ (cycloalkenyl)(C₁₋₄)alkyl, optionallysubstituted with 1, 2, or 3 substituents, each independently selectedfrom the group consisting of hydroxy, C₁₋₄ alkyl, halo, halo(C₁₋₄)alkyl,amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, andC₁₋₄ alkoxycarbonyl, and R³, R^(4a1), and R^(4b1) are as defined abovein connection with Formula I-A,

In another embodiment, Compounds of the invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R² is C₃₋₇(cycloalkyl)(C₁₋₄)alkyl or C₃₋₇ (cycloalkenyl)(C₁₋₄)alkyl, optionallysubstituted with 1, 2, or 3 substituents, each independently selectedfrom the group consisting of hydroxy, C₁₋₄ alkyl, halo, halo(C₁₋₄)alkyl,amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, andC₁₋₄ alkoxycarbonyl, and R¹, R³, R^(4a), and R^(4b) are as defined abovein connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R² iscyclopropyl(C₁₋₄)alkyl, cyclobutyl(C₁₋₄)alkyl, cyclopentyl(C₁₋₄)alkyl,or cyclohexyl(C₁₋₄)alkyl, optionally substituted with 1, 2, or 3substituents, each independently selected from the group consisting ofhydroxy, C₁₋₄ alkyl, halo, halo(C₁₋₄)alkyl, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl, andR¹, R³, R^(4a1), and R^(4b1) are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R² iscyclopropyl(C₁₋₄)alkyl, cyclobutyl(C₁₋₄)alkyl, cyclopentyl(C₁₋₄)alkyl,or cyclohexyl(C₁₋₄)alkyl, optionally substituted with 1, 2, or 3substituents, each independently selected from the group consisting ofhydroxy, C₁₋₄ alkyl, halo, halo(C₁₋₄)alkyl, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, alkoxy, and alkoxycarbonyl, and R¹, R³,R^(4a), and R^(4b) are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R² is cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl, optionallysubstituted with 1, 2, or 3 substituents, each independently selectedfrom the group consisting of hydroxy, C₁₋₄ alkyl, halo, halo(C₁₋₄)alkyl,amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, alkoxy, and C₁₋₄alkoxycarbonyl, and R¹, R³, R^(4a1), and R^(4b1) are as defined above inconnection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R² is cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl, optionallysubstituted with 1, 2, or 3 substituents, each independently selectedfrom the group consisting of hydroxy, C₁₋₄ alkyl, halo, halo(C₁₋₄)alkyl,amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, andC₁₋₄ alkoxycarbonyl, and R¹, R³, R^(4a1), and R^(4b1) are as definedabove in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R³ is hydrogen, and R¹,R², R^(4a1), and R^(4b1) are as defined above in connection with FormulaI-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R³ is hydrogen, and R¹,R², R^(4a), and R^(4b) are as defined above in connection with FormulaI.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R³ is hydroxy, and R¹,R², R^(4a1), and R^(4b1) are as defined above in connection with FormulaI-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R³ is hydroxy, and R¹,R², R^(4a), and R^(4b) are as defined above in connection with FormulaI.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-I,i.e., R^(4a1) is:

and R¹, R², R³, R^(4b1), R^(5a), R^(5b), n, and R⁶ are as defined abovein connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-I, i.e.,R^(4a) is:

and R¹, R², R³, R^(4b), R^(5a), R^(5b), n, and R⁶ are as defined abovein connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-I,R^(5a) and R^(5b) are each hydrogen, and R¹, R², R³, R^(4b1), n, and R⁶are as defined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-I,R^(5a) and R^(5b) are each hydrogen, and R¹, R², R³, R^(4b), n, and R⁶are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-I and nis 1, and R¹, R², R³, R^(4b1), R^(5a), R^(5b), and R⁶ are as definedabove in connection with Formula I-A.

In another embodiment. Compounds of the invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-I and nis 1, and R¹, R², R³, R^(4b), R^(5a), R^(5b), and R⁶ are as definedabove in connection with Formula I.

In another embodiment, Compounds of the invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-I andR⁶ is selected from the group consisting of hydrogen and C₁₋₄ alkyl, andR¹, R², R³, R^(4b1), R^(5a), R^(5b), and n are as defined above inconnection with Formula I-A,

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-I and R⁶is selected from the group consisting of hydrogen and C₁₋₄ alkyl, andR¹, R², R³, R^(4a), R^(5a), R^(5b), and n are as defined above inconnection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-I andR⁶ is hydrogen, and R¹, R², R³, R^(4b1), R^(5a), R^(5b), and n are asdefined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-I and R⁶is hydrogen, and R¹, R², R³, R^(4b), R^(5a), R^(5b), and n are asdefined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-I.R^(5a) and R^(5b) are each hydrogen, n is 1, and R⁶ is hydrogen, and R¹,R², R³, and R^(4b1) are as defined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented h any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-I,R^(5a) and R^(5b) are each hydrogen, n is 1, and R⁶ is hydrogen, and R¹,R², R³, and R^(4b) are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-I,R^(4b1) is hydrogen, R^(5a) and R^(5b) are each hydrogen, n is 1, and R⁶is hydrogen, and R¹, R², and R³ are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-I,R^(4b) is hydrogen, R^(5a) and R^(5b) are each hydrogen, n is 1, and R⁶is hydrogen, and R¹, R², and R³ are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) and R^(4b1) areboth R^(4a)-I, R^(5a) and R^(5b) are each hydrogen, n is 1, and R⁶ ishydrogen, and R¹, R², and R³ are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) and R^(4b) areboth R^(4a)-I, R^(5a) and R^(5b) are each hydrogen, n is 1, and R⁶ ishydrogen, and R¹, R², and R³ are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-II,i.e., R^(4a1) is:

and R¹, R², R³, R^(4b1), R^(5c), R^(5d), R⁷, R^(8a), R^(8b), o, and R⁹are as defined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-II,i.e., R^(4a) is:

and R¹, R², R³, R^(4b), R^(5c), R^(5d), R⁷, R^(8a), R^(8b), o, and R⁹are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-II andR^(5c) and R^(5d) are each hydrogen, and R¹, R², R³, R^(4b1), R⁷,R^(8a), R^(8b), o, and R⁹ are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-II andR^(5c) and R^(5d) are each hydrogen, and R¹, R², R³, R^(4b), R⁷, R^(8a),R^(8b), o, and R⁹ are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-II ando is 1, and R¹, R², R³, R^(4b1), R^(5c), R^(5d), R⁷, R^(8a), R^(8b), andR⁹ are as defined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-11 and ois 1, and R¹, R², R³, R^(4b), R^(5c), R^(5d), R⁷, R^(8a), R^(8b), and R⁹are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-II andR^(8b) is hydrogen, and R¹, R², R³, R^(4b1), R^(5c), R^(5d), R⁷, R^(8a),o, and R⁹ are as defined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-II andR^(8b) is hydrogen, and R¹, R², R³, R^(4b), R^(5c), R^(5d), R⁷, R^(8a),o, and R⁹ are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is:

and R¹, R², R³, R^(4b1), R⁷, R^(8a), and R⁹ are as defined above inconnection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is:

and R¹, R², R³, R^(4b), R⁷, R^(8a), and R⁹ are as defined above inconnection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is:

and R¹, R², R³, R^(4b1), R⁷, R^(8a), and R⁹ are as defined above inconnection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is:

and R¹, R², R³, R^(4b), R⁷, R^(8a), and R⁹ are as defined above inconnection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-II,R^(8a) is hydrogen or C₁₋₄ alkyl, wherein the alkyl is optionallysubstituted with 1 or 2 substituents, each independently selected fromthe group consisting of hydroxy, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl are optionally substitutedwith 1, 2, or 3 independently selected R^(11a) groups, and R^(8b) ishydrogen, and R¹, R², R³, R^(4b1), R^(5c), R^(5d), R⁷, o, R⁹, R^(11a)are as defined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-II,R^(8a) is hydrogen or C₁₋₄ alkyl, wherein the alkyl is optionallysubstituted with 1 or 2 substituents, each independently selected fromthe group consisting of hydroxy, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl are optionally substitutedwith 1, 2, or 3 independently selected R¹¹ groups, and R^(8b) ishydrogen, and R¹, R², R³, R^(4b), R^(5c), R^(5d), R⁷, o, R⁹, R¹¹ are asdefined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-IV orR^(4a)-V, R^(4b1) is hydrogen, and R^(8a) is hydrogen or C₁₋₄ alkyl,wherein the alkyl is optionally substituted with 1 or 2 substituents,each independently selected from the group consisting of hydroxy, halo,haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein the aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl are optionally substituted with 1, 2, or 3 independentlyselected R^(11a) groups, and R¹, R², R³, R⁷, R⁹, and R^(11a) are asdefined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-IV orR^(4a)-V, R^(4b) is hydrogen, and R^(8a) is hydrogen or C₁₋₄ alkyl,wherein the alkyl is optionally substituted with 1 or 2 substituents,each independently selected from the group consisting of hydroxy, halo,haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein the aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl are optionally substituted with 1, 2, or 3 independentlyselected R¹¹ groups, and R¹, R², R³, R⁷, R⁹, and R¹¹ are as definedabove in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-II,R^(8a) is C₁₋₄ alkyl optionally substituted with 1 substituent selectedfrom the group consisting of aryl, hydroxy, halo, haloalkyl, amino,alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, andaminocarbonyl, wherein the aryl is optionally substituted with 1, 2, or3 independently selected R^(11a) groups, and R^(8b) is hydrogen, and R¹,R², R³, R^(4b1), R^(5c), R^(5d), R⁷, o, R⁹, R^(11a) are as defined abovein connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-II,R^(8a) is C₁₋₄ alkyl optionally substituted with 1 substituent selectedfrom the group consisting of aryl, hydroxy, halo, haloalkyl, amino,alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, andaminocarbonyl, wherein the aryl is optionally substituted with 1, 2, or3 independently selected R¹¹ groups, and R^(8b) is hydrogen, and R¹, R²,R³, R^(4b), R^(5c), R^(5d), R⁷, o, R⁹, R^(11a) are as defined above inconnection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-IV orR^(4a)-V, R^(4b1) is hydrogen, and R^(8a) is C₁₋₄ alkyl optionallysubstituted with 1 substituent selected from the group consisting ofaryl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino,carboxy, alkoxy, alkoxycarbonyl, and aminocarbonyl, wherein the aryl isoptionally substituted with 1, 2, or 3 independently selected R^(11a)groups, and R¹, R², R³, R⁷, R⁹, and R^(11a) are as defined above inconnection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-IV orR^(4a)-V, R^(4b) is hydrogen, and R^(8a) is C₁₋₄ alkyl optionallysubstituted with 1 substituent selected from the group consisting ofaryl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino,carboxy, alkoxy, alkoxycarbonyl, and aminocarbonyl, wherein the aryl isoptionally substituted with 1, 2, or 3 independently selected R¹¹groups, and R¹, R², R³, R⁷, R⁹, and R¹¹ are as defined above inconnection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-II,R^(4b1) is hydrogen, and R⁷ is hydrogen, and R¹, R², R³, R^(5c), R^(5d),R^(8a), o, and R⁹ are as defined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-IV orR^(4a)-V, R^(4b) is hydrogen, and R⁷ is hydrogen, and R¹, R², R³,R^(8a), and R⁹ are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-II,R^(4b) is hydrogen, and R⁷ is hydrogen, and R¹, R², R³, R^(5c), R^(5d),R^(8a), o, and R⁹ are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-IV orR^(4a)-V, R^(4b1) is hydrogen, and R⁷ is hydrogen, and R¹, R², R³,R^(8a), and R⁹ are as defined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-IV orR^(4a)-V, R^(4b) is hydrogen, and R⁷ is hydrogen, and R¹, R², R³,R^(8a), and R⁹ are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-II,R^(4b1) is hydrogen, R^(8b) is hydrogen, and R⁷ and R^(8a) takentogether with the atoms to which they are attached form a 5-memberedheterocyclo, and R¹, R², R³, R^(5c), R^(5d), o, and R⁹ are as definedabove in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-II,R^(4b) is hydrogen, R^(8b) is hydrogen, and R⁷ and R^(8a) taken togetherwith the atoms to which they are attached form a 5-membered heterocyclo,and R¹, R², R³, R^(5c), R^(5d), o, and R⁹ are as defined above inconnection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-IV orR^(4a)-V, R^(4b1) is hydrogen, and R⁷ and R^(8a) taken together with theatoms to which they are attached form a 5-membered heterocyclo, and R¹,R², R³, and R⁹ are as defined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a1)-IV orR^(4a)-V, R^(4b) is hydrogen, and R⁷ and R^(8a) taken together with theatoms to which they are attached form a 5-membered heterocyclo, and R¹,R², R³, and R⁹ are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-II,R^(4b1) is hydrogen, R⁷ is hydrogen, R^(8b) is hydrogen, and R⁹ ishydrogen, and R¹, R², R³, R^(5c), R^(5d), R^(8a), and o are as definedabove in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-II,R^(4b) is hydrogen, R⁷ is hydrogen, R^(8b) is hydrogen, and R⁹ ishydrogen, and R¹, R², R³, R^(5c), R^(5d), R^(8a), and o are as definedabove in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-IV orR^(4a)-V, R^(4b1) is hydrogen, R⁷ is hydrogen, and R⁹ is hydrogen andR¹, R², R³, and R^(8a) are as defined above in connection with FormulaI-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-IV orR^(4a)-V, R^(4b) is hydrogen, R⁷ is hydrogen, and R⁹ is hydrogen and R¹,R², R³, and R^(8a) are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-II,R^(4b) is hydrogen, R^(8b) is hydrogen, R⁷ and R^(8a) taken togetherwith the atoms to which they are attached form a 5-membered heterocyclo,and R⁹ is hydrogen, and R¹, R², R³, R^(5c), R^(5d), and o are as definedabove in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-II,R^(4b) is hydrogen, R^(8b) is hydrogen, R⁷ and R^(8a) taken togetherwith the atoms to which they are attached form a 5-membered heterocyclo,and R⁹ is hydrogen, and R¹, R², R³, R^(5c), R^(5d), and o are as definedabove in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-IV orR^(4a)-V, R^(4b1) is hydrogen, R⁷ and R^(8a) taken together with theatoms to which they are attached form a 5-membered heterocyclo, and R⁹is hydrogen, and R¹, R², and R³ are as defined above in connection withFormula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-IV orR^(4a)-V, R^(4b) is hydrogen, R⁷ and R^(8a) taken together with theatoms to which they are attached form a 5-membered heterocyclo, and R⁹is hydrogen, and R¹, R², and R³ are as defined above in connection withFormula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-II,R^(4b1) is hydrogen, R⁷ is hydrogen, R^(8a) is C₁₋₄ alkyl, R^(8b) ishydrogen, and R⁹ is hydrogen, and R¹, R², R³, R^(5c), R^(5d), and o areas defined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-II,R^(4b) is hydrogen, R⁷ is hydrogen, R^(8a) is C₁₋₄ alkyl, R^(8b) ishydrogen, and R⁹ is hydrogen, and R¹, R², R³, R^(5c), R^(5d), and o areas defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-IV orR^(4a)-V, R^(4b1) is hydrogen, R⁷ is hydrogen, R^(8a) is C₁₋₄ alkyl, andR⁹ is hydrogen and R¹, R², and R³ are as defined above in connectionwith Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-IV orR^(4a)-V, R^(4b) is hydrogen, R⁷ is hydrogen, R^(8a) is C₁₋₄ alkyl, andR⁹ is hydrogen and R¹, R², and R³ are as defined above in connectionwith Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is selected fromthe group consisting of:

and R^(4b1) is hydrogen, and R¹, R², and R³ are as defined above inconnection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is selected fromthe group consisting of:

and R^(4b) is hydrogen, and R¹, R², and R³ are as defined above inconnection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-III,i.e., R^(4a1) is:

and R¹, R², R³, R^(4b1), R^(5e), R^(5f), p, and R¹⁰ are as defined abovein connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-III,i.e., R^(4a) is:

and R¹, R², R³, R^(4b), R^(5e), R^(5f), p, and R¹⁰ are as defined abovein connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-III andR^(5e) and R^(5f) are each hydrogen, and R¹, R², R³, R^(4b1), p, and R¹⁰are as defined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-III andR^(5e) and R^(5f) are each hydrogen, and R¹, R², R³, R^(4b), p and R¹⁰are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-III andp is 1, and R¹, R², R³, R^(4b1), R^(5e), R^(5f), and R¹⁰ are as definedabove in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-III andp is 1, and R¹, R², R³, R^(4b), R^(5e), R^(5f), and R¹⁰ are as definedabove in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-III andR¹⁰ is hydrogen, or alkyl, cycloalkyl, aryl, heteroaryl, or arylalkyl,any of which is optionally substituted with 1, 2, or 3 substituents,each independently selected from the group consisting of hydroxy, alkyl,halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein the aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl are optionally substituted with 1, 2, or 3 independentlyselected R^(11a) groups, and R¹, R², R³, R^(4b1), R^(5e), R^(5f), p, andR^(11a) are as defined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-III andR¹⁰ is hydrogen, or alkyl, cycloalkyl, aryl, heteroaryl, or arylalkyl,any of which is optionally substituted with 1, 2, or 3 substituents,each independently selected from the group consisting of hydroxy, alkyl,halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein the aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl are optionally substituted with 1, 2, or 3 independentlyselected R¹¹ groups, and R¹, R², R³, R^(4b), R^(5e), R^(5f), p, and R¹¹are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-III,R^(4b1) is hydrogen, R^(5e) and R^(5f) are hydrogen, p is 1, and R¹⁰ ishydrogen, or alkyl, cycloalkyl, aryl, heteroaryl, or arylalkyl, any ofwhich is optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, alkyl,halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein the aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl are optionally substituted with 1, 2, or 3 independentlyselected R^(11a) groups, and R¹, R², R³, and R^(11a) are as definedabove in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-III,R^(4b) is hydrogen, R^(5e) and R^(5f) are hydrogen, p is 1, and R¹⁰ ishydrogen, or alkyl, cycloalkyl, aryl, heteroaryl, or arylalkyl, any ofwhich is optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, alkyl,halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein the aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl are optionally substituted with 1, 2, or 3 independentlyselected R¹¹ groups, and R¹, R², R³, and R¹¹ are as defined above inconnection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is R^(4a)-III,R^(4b1) is hydrogen, R^(5e) and R^(5f) are hydrogen, p is 1, and R¹⁰ isselected from the group consisting of:

and R¹, R², and R³ are as defined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a) is R^(4a)-III,R^(4b) is hydrogen, R^(5e) and R^(5f) are hydrogen, p is 1, and R¹⁰ isselected from the group consisting of:

and R¹, R², and R³ are as defined above in connection with Formula I.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is C₃-C₆ alkyl,R^(4b1) is hydrogen, and R¹, R², and R³ are as defined in connectionwith Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is arylalkyl,R^(4b1) is hydrogen, and R¹, R², and R³ are as defined in connectionwith Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is(cycloalkyl)alkyl, R^(4b1) is hydrogen, and R¹, R², and R³ are asdefined in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is C₃-C₆ alkoxy,R^(4b1) is hydrogen, and R¹, R², and R³ are as defined in connectionwith Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is aralkyloxy,R^(4b1) is hydrogen, and R¹, R², and R³ are as defined in connectionwith Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is —N(H)COR^(4c),R^(4b1) is hydrogen, and R¹, R², R³, and R^(4c) are as defined inconnection with Formula I-A. In another embodiment, R^(4c) is alkyl,cycloalkyl, heterocyclo, arylalkyl, or aryl.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is—CH₂C(═O)NR^(4d)R^(4e), R^(4b1) is hydrogen, and R¹, R², R³, R^(4d) andR^(4e) are as defined in connection with Formula I-A. In anotherembodiment, R^(4d) and R^(4e) are taken together with the nitrogen atomto which they are attached form a 4- to 8-membered heterocyclo, whereinthe heterocyclo is optionally substituted with 1 or 2 substituents, eachindependently selected from the group consisting of alkyl, hydroxy,halo, haloalkyl, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl,arylalkyl, and aryl, wherein the alkyl, arylalkyl, and aryl areoptionally substituted with 1, 2, or 3 independently selected R^(11a)groups. In another embodiment, R^(4d) and R^(4e) are taken together withthe nitrogen atom to which they are attached form a 5- or 6-memberedheterocyclo, wherein the heterocyclo is optionally substituted with onesubstituent, independently selected from the group consisting of alkyl,arylalkyl, and aryl, wherein the alkyl, arylalkyl, and aryl areoptionally substituted with 1, 2, or 3 independently selected R^(11a)groups.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is:

i.e., R^(4d) and R^(4e) are taken together with the nitrogen atom towhich they are attached form a piperazine, wherein the NH is optionallysubstituted with one substituent independently selected from the groupconsisting of alkyl, arylalkyl, and aryl, wherein the alkyl, arylalkyl,and aryl are optionally substituted with 1, 2, or 3 independentlyselected R^(11a) groups.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) is—N(H)SO₂R^(4f), R^(b1) is hydrogen, and R¹, R², R³, and R^(4f) are asdefined in connection with Formula I-A. In another embodiment, R^(4f) isalkyl or aryl, wherein the aryl is optionally substituted with 1, 2, or3 independently selected R^(11a) groups.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(4a1) and R^(4b1) aretaken together to form an alkenyl, and R¹, R², and R³ are as defined inconnection with Formula I-A. By way of example, R^(4a1) and R^(4b1) ofFormula III-A are taken together to form an alkenyl to give a compoundhaving Formula XIV:

and the pharmaceutically acceptable salts and solvates thereof, whereinR is hydrogen alkyl, or cycloalkyl, and R¹, R², and R³ are as defined inconnection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula XV or Formula XVI:

and the pharmaceutically acceptable salts and solvates thereof, wherein:

R¹ is selected from the group consisting of OH and methoxy;

R² is selected from the group consisting of —CH₃ and —CH₂(cyclopropyl);

R³ is selected from the group consisting of hydrogen and OH; and

R^(4a1) is as defined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by Formula XV or Formula XVI, and the pharmaceuticallyacceptable salts and solvates thereof, wherein:

R¹ is selected from the group consisting of OH and methoxy;

R² is selected from the group consisting of —CH₃ and —CH₂(cyclopropyl);

R³ is selected from the group consisting of hydrogen and OH; and

R^(4a1) is selected from the group consisting of C₃-C₆ alkyl,(cycloalkyl)alkyl, C₃-C₆ alkoxy, aralkyloxy, —N(H)COR^(4c),—CH₂C(═O)NR^(4d)R^(4e), —N(H)SO₂R^(4f),

wherein R^(4c), R^(4d), R^(4e), R^(4f), R^(8a) and p are defined abovein connection with Formula I-A.

In another embodiment, Compounds of the Invention are compounds of Table1, and the pharmaceutically acceptable salts and solvates thereof.

TABLE 1 Compound No. Structure 1

8

9

10

12

13

15

16

17

18

19

In another embodiment, Compounds of the Invention are compounds of Table1A, and the pharmaceutically acceptable salts and solvates thereof.

TABLE 1A Compound No. Structure 46

48

49

50

54

58

59

60

61

75

In another embodiment, Compounds of the Invention are compounds of Table1B, and the pharmaceutically acceptable salts and solvates thereof.

TABLE 1B Compound No. Structure 23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

42

43

62

64

65

66

67

68

69

70

71

72

73

74

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

The chemical names of the compound examples of Tables 1, 1A, and 1B areprovided in Table 2.

TABLE 2 Compound No. Chemical Name 1 ethyl2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetate 82-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetic acid 92-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetic acid 102,2′-((4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-7,7-diyl)diacetic acid 122,2′-((4bR,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-7,7-diyl)diacetic acid 13(S)-2-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamido)propanoic acid 15(S)-2-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamido)propanoic acid 16(S)-1-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetyl)pyrrolidine-2-carboxylic acid 17(S)-1-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetyl)pyrrolidine-2-carboxylic acid 18(S)-2-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamido)-4-methylpentanoic acid 19(S)-2-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamido)-4-methylpentanoic acid 23(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-7-isobutoxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 24(4bR,7S,8aS,9R)-7-(benzyloxy)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 25(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-7,8a-dihydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 26N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)isobutyramide 27N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)isobutyramide 28N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamide 29N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)propionamide 30N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-4-methylpentanamide 31N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-5-methylhexanamide 32N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)pivalamide 33N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-3-methylbutanamide 34N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)cyclopropanecarboxamide 35N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)cyclopentanecarboxamide 36N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)benzamide 37(S)-N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-2-methylbutanamide 38N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)cyclohexanecarboxamide 42N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)ethanesulfonamide 43N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)benzenesulfonamide 46(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-7-(2-hydroxyethyl)-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 48(4bR,7S,8aS,9R)-7-(2-(benzyloxy)ethyl)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 49(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-7-(2-methoxyethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 50(4bR,7S,8aS,9R)-7-(2-(benzyloxy)ethyl)-8a-hydroxy-3-methoxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 54(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-hydroxyethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 58(4bR,7S,8aS,9R)-3-(benzyloxy)-11-(cyclopropylmethyl)-8a-hydroxy-7-(2-hydroxyethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 59 ethyl2-((4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetate 602-((4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7- yl)aceticacid 61 2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7- yl)aceticacid 62 (4bR,8aS,9R,E)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-7-(3-methylbutylidene)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 64(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-isopentyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 65(4bR,7S,8aS,9R)-7-(cyclopentylmethyl)-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 66(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-methylbutyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 67(4bR,7S,8aS,9R)-7-butyl-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)- one 68(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-neopentyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 69(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-isobutyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 70(4bR,7S,8aS,9R)-7-(cyclohexylmethyl)-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 71(4bR,7S,8aS,9R)-7-benzyl-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 72(4bS,7S,8aR,9R)-11-(cyclopropylmethyl)-7-isopropyl-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)- one 73(4bS,7S,8aR,9R)-11-(cyclopropylmethyl)-3-hydroxy-7-isopropyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)- one 74(4bS,7R,8aR,9R)-11-(cyclopropylmethyl)-3-hydroxy-7-isopropyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)- one 75(2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetyl)-L-alanine 76(4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-7-(2-oxo-2-(piperidin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 77(4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-7-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 78(4bR,7R,8aS,9R)-8a-hydroxy-7-(2-(4-hydroxypiperidin-1-yl)-2-oxoethyl)-3-methoxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 79(4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-7-(2-morpholino-2-oxoethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 80(4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-7-(2-oxo-2-(piperidin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 81(4bR,7R,8aS,9R)-3,8a-dihydroxy-7-(2-(4-hydroxypiperidin-1-yl)-2-oxoethyl)-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 822-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-N-isobutylacetamide 83N-benzyl-2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamide 84N-(cyclopropylmethyl)-2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamide 852-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-N-(2-hydroxyethyl)acetamide 862-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-N-(3-hydroxypropyl)acetamide 872-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-N-(2-hydroxyethyl)acetamide 882-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-N-(3-hydroxypropyl)acetamide 89(4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-7-(2-oxo-2-(piperazin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 90(4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-7-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 91(4bR,7R,8aS,9R)-7-(2-(4-benzylpiperazin-1-yl)-2-oxoethyl)-3,8a-dihydroxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 92(4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-7-(2-oxo-2-(4-phenylpiperazin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 93(4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-oxo-2-(piperazin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 94(4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 95(4bR,7R,8aS,9R)-7-(2-(4-benzylpiperazin-1-yl)-2-oxoethyl)-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 96(4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-oxo-2-(4-phenylpiperazin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 97N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamide 98 N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)propionamide 99 N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)isobutyramide 100 N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)pivalamide 101 N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-4-methylpentanamide 102N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-5-methylhexanamide 103N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)cyclohexanecarboxamide 104(4bS,7S,8aR,9R)-11-(cyclopropylmethyl)-3-hydroxy-7-isopentyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)- one 105(4bS,7S,8aR,9R)-7-(cyclopentylmethyl)-11-(cyclopropylmethyl)-3-hydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 106(4bR,7S,8aS,9R)-3,8a-dihydroxy-7-isopentyl-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one 107(4bS,7S,8aR,9R)-7-(cyclopentylmethyl)-3-hydroxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)- one 108N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)methanesulfonamide 109N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)piperidine-4-carboxamide 110N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-2-(dimethylamino)acetamide

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-A-XIII-A, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R¹ is —O—PG, wherein PGis a hydroxyl protecting group, and R², R³, R^(4a1), and R^(4b1) are asdefined above in connection with Formula I-A.

In another embodiment, Compounds of the Invention are compoundsrepresented by any one of Formulae I-XIII, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R¹ is —O—PG, wherein PGis a hydroxyl protecting group, and R², R³, R^(4a), and R^(4b) are asdefined above in connection with Formula I.

In one aspect, the present disclosure is drawn to the followingparticular embodiments:

Embodiment I

A compound having the Formula I-A:

or a pharmaceutically acceptable salt or solvate thereof,wherein:

R¹ is hydrogen, OH, halo, cyano, carboxy, or aminocarbonyl; or alkyl,alkenyl, alkynyl, alkoxy, alkenyloxy, or alkynyloxy, any of which isoptionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, halo, haloalkyl, amino,alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionallysubstituted with 1, 2, or 3 independently selected R^(11a) groups; or—O—PG, wherein PG is a hydroxyl protecting group;

R² is:

-   -   (a) hydrogen or carboxamido; or    -   (b) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl,        (cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl,        heteroarylalkyl, alkylcarbonyl, alkoxycarbonyl,        (arylalkoxy)carbonyl, or (heteroarylalkoxy)carbonyl, any of        which is optionally substituted with 1, 2, or 3 substituents,        each independently selected from the group consisting of        hydroxy, alkyl, halo, haloalkyl, amino, alkylamino,        dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,        heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl,        heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are        optionally substituted with 1, 2, or 3 independently selected        R^(11a) groups;

R³ is hydrogen, OH, or halo; or alkoxy, alkylamino, or dialkylamino, anyof which is optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxyl, halo,haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein the aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl are optionally substituted with 1, 2, or 3 independentlyselected R^(11a) groups;

R^(4a1) is selected from the group consisting of C₃-C₆ alkyl, arylalkyl,(cycloalkyl)alkyl, C₃-C₆ alkoxy, aralkyloxy, —N(H)COR^(4c),—CH₂C(═O)NR^(4d)R^(4e), —N(H)SO₂R^(4f),

R^(4b1) is selected from the group consisting of hydrogen and R^(4a)-I;or

R^(4a1) and R^(4b1) taken together form an alkenyl,

R^(4c) is alkyl, cycloalkyl, heterocyclo, arylalkyl, or aryl, any ofwhich is optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, alkyl,halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein the aryl and cycloalkyl are optionally substitutedwith 1, 2, or 3 independently selected R^(11a) groups;

R^(4d) is hydrogen; or alkyl, cycloalkyl, arylalkyl, or aryl, any ofwhich is optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, alkyl,halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein the aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl are optionally substituted with 1, 2, or 3 independentlyselected R^(11a) groups;

R^(4e) is hydrogen; or alkyl, optionally substituted with 1, 2, or 3substituents, each independently selected from the group consisting ofhydroxy, alkyl, halo, haloalkyl, amino, alkylamino, dialkylamino,carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo,cycloalkyl, and cycloalkenyl; or

R^(4d) and R^(4e) taken together with the nitrogen atom to which theyare attached form a 4- to 8-membered heterocyclo, wherein theheterocyclo is optionally substituted with 1 or 2 substituents, eachindependently selected from the group consisting of alkyl, hydroxy,halo, haloalkyl, amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl,arylalkyl, and aryl, wherein the alkyl, arylalkyl, and aryl areoptionally substituted with 1, 2, or 3 independently selected R^(11a)groups;

R^(4f) is alkyl, cycloalkyl, arylalkyl, or aryl, any of which isoptionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, alkyl, halo, haloalkyl,amino, alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryland cycloalkyl are optionally substituted with 1, 2, or 3 independentlyselected R^(11a) groups;

-   -   each R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), and R^(5f) is        independently selected from the group consisting of hydrogen and        alkyl;

R⁶ is hydrogen or alkyl;

R⁷ is hydrogen or alkyl;

R^(8a) is hydrogen or alkyl, cycloalkyl, cycloalkenyl, heterocyclo,aryl, heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl,(heterocyclo)alkyl, arylalkyl, or heteroarylalkyl, any of which isoptionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, alkyl, halo, haloalkyl,amino, alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionallysubstituted with 1, 2, or 3 independently selected R^(11a) groups;

R^(8b) is hydrogen or alkyl, wherein the alkyl is optionally substitutedwith 1, 2, or 3 substituents, each independently selected from the groupconsisting of alkyl, hydroxy, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, and aminocarbonyl; or

R^(8a) and R^(8b) taken together with the carbon atom to which they areattached form a 3- to 8-membered cycloalkyl; or

R⁷ and R^(8b) taken together with the atoms to which they are attachedform a 4- to 8-membered heterocyclo, wherein the heterocyclo isoptionally substituted with 1 or 2 substituents, each independentlyselected from the group consisting of alkyl, hydroxy, halo, haloalkyl,amino, alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, andaminocarbonyl;

R⁹ is hydrogen or alkyl;

R¹⁰ is hydrogen, or alkyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl,heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (heterocyclo)alkyl,arylalkyl, or heteroarylalkyl, any of which is optionally substitutedwith 1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, alkyl, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl are optionally substitutedwith 1, 2, or 3 independently selected R^(11a) groups;

each R^(11a) is independently selected from the group consisting ofhydroxy, halo, alkyl, haloalkyl, cyano, nitro, amino, alkylamino,dialkylamino, carboxy, alkoxy, and alkoxycarbonyl;

n is 1, 2, or 3;

o is 1, 2, or 3; and

p is 1, 2, or 3.

Embodiment II

The compound of Embodiment I, or a pharmaceutically acceptable salt orsolvate thereof, wherein:

R^(4a1) is selected from the group consisting of:

andR^(4b1) is selected from the group consisting of hydrogen and R^(4a)-I.

Embodiment III

The compound of Embodiment I or II, having the Formula II-A:

or a pharmaceutically acceptable salt or solvate thereof.

Embodiment IV

The compound of Embodiment III, having the Formula III-A:

or a pharmaceutically acceptable salt or solvate thereof.

Embodiment V

The compound of Embodiment IV, having the Formula IV-A:

or a pharmaceutically acceptable salt or solvate thereof.

Embodiment VI

The compound of Embodiment IV, having the Formula V-A:

or a pharmaceutically acceptable salt or solvate thereof.

Embodiment VII

The compound of Embodiment III, having the Formula VI-A:

or a pharmaceutically acceptable salt or solvate thereof.

Embodiment VIII

The compound of Embodiment III, having the Formula VII-A:

or a pharmaceutically acceptable salt or solvate thereof.

Embodiment IX

The compound of Embodiment I or II, having the Formula VIII-A:

or a pharmaceutically acceptable salt or solvate thereof.

Embodiment X

The compound of Embodiment IX, having the Formula IX-A:

or a pharmaceutically acceptable salt or solvate thereof.

Embodiment XI

The compound of Embodiment X, having the Formula X-A:

or a pharmaceutically acceptable salt or solvate thereof.

Embodiment XII

The compound of Embodiment X, having the Formula XI-A:

or a pharmaceutically acceptable salt or solvate thereof.

Embodiment XIII

The compound of Embodiment IX, having the Formula XII-A:

or a pharmaceutically acceptable salt or solvate thereof.

Embodiment XIV

The compound of Embodiment IX, having the Formula XIII-A:

or a pharmaceutically acceptable salt or solvate thereof

Embodiment XV

The compound of any one of Embodiments I-IV, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R¹ is hydrogen, OH, halo,cyano, carboxy, or aminocarbonyl; or alkyl, alkenyl, alkynyl, alkoxy,alkenyloxy, or alkynyloxy, any of which is optionally substituted with1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino,carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo,cycloalkyl, and cycloalkenyl, wherein the aryl, heteroaryl, heterocyclo,cycloalkyl, and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R^(11a) groups.

Embodiment XVI

The compound of any one of Embodiments I-XV, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R¹ is OH or unsubstitutedC₁₋₆ alkoxy.

Embodiment XVII

The compound of any one of Embodiments I-XVI, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R² is hydrogen orcarboxamido.

Embodiment XVIII

The compound of any one of Embodiments I-XVI, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R² is alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl,(cycloalkyl)alkyl, (cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl,heteroarylalkyl, alkylcarbonyl, alkoxycarbonyl, (arylalkoxy)carbonyl, or(heteroarylalkoxy)carbonyl, any of which is optionally substituted with1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, alkyl, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl are optionally substitutedwith 1, 2, or 3 independently selected R^(11a) groups.

Embodiment XIX

The compound of Embodiment XVIII, or a pharmaceutically acceptable saltor solvate thereof, wherein R² is C₃₋₇ (cycloalkyl)(C₁₋₄) or C₃₋₇(cycloalkenyl)(C₁₋₄)alkyl, optionally substituted with 1, 2, or 3substituents, each independently selected from the group consisting ofhydroxy, C₁₋₄ alkyl, halo, halo(C₁₋₄)alkyl, amino, C₁₋₄ alkylamino,di(C₁₋₄)alkylamino, carboxy, C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl.

Embodiment XX

The compound of Embodiment XIX, or a pharmaceutically acceptable salt orsolvate thereof, wherein R² is cyclopropyl(C₁₋₄)alkyl,cyclobutyl(C₁₋₄)alkyl, cyclopentyl(C₁₋₄)alkyl, or cyclohexyl(C₁₋₄)alkyl,optionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, C₁₋₄ alkyl, halo,halo(C₁₋₄)alkyl, amino, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, carboxy,C₁₋₄ alkoxy, and C₁₋₄ alkoxycarbonyl.

Embodiment XXI

The compound of any one of Embodiments I-XX, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R³ is hydrogen.

Embodiment XXII

The compound of any one of Embodiments I-XX, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R³ is hydroxy.

Embodiment XXIII

The compound of any one of Embodiments I-XXII, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(4a1) is C₃-C₆ alkyl.

Embodiment XXIV

The compound of any one of Embodiments I-XXII, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(4a1) is arylalkyl.

Embodiment XXV

The compound of any one of Embodiments I-XXII, or a pharmaceuticallyacceptable salt or solvate thereof wherein R^(4a1) is (cycloalkyl)alkyl.

Embodiment XXVI

The compound of any one of Embodiments I-XXII, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(4a1) is C₃-C₆ alkoxy.

Embodiment XXVII

The compound of any one of Embodiments I-XXII, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(4a1) is aralkyloxy.

Embodiment XXVIII

The compound of any one of Embodiments I-XXII, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(4a1) is N(H)COR^(4c).

Embodiment XXIX

The compound of Embodiment XXVIII, or a pharmaceutically acceptable saltor solvate thereof, wherein R^(4c) is alkyl, cycloalkyl, heterocyclo,arylalkyl, or aryl.

Embodiment XXX

The compound of any one of Embodiments I-XXII, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(4a1) is—CH₂C(═O)NR^(4d)R^(4e).

Embodiment XXXI

The compound of Embodiment XXX, or a pharmaceutically acceptable salt orsolvate thereof, wherein R^(4d) and R^(4e) are taken together with thenitrogen atom to which they are attached form a 4- to 8-memberedheterocyclo, wherein the heterocyclo is optionally substituted with 1 or2 substituents, each independently selected from the group consisting ofalkyl, hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino,alkoxy, aminocarbonyl, arylalkyl, and aryl, wherein the alkyl,arylalkyl, and aryl are optionally substituted with 1, 2, or 3independently selected R^(11a) groups.

Embodiment XXXII

The compound of Embodiment XXXI, or a pharmaceutically acceptable saltor solvate thereof, wherein R^(4d) and R^(4e) are taken together withthe nitrogen atom to which they are attached form a 5- or 6-memberedheterocyclo, wherein the heterocyclo is optionally substituted with onesubstituent, independently selected from the group consisting of alkyl,arylalkyl, and aryl, wherein the alkyl, arylalkyl, and aryl areoptionally substituted with 1, 2, or 3 independently selected R^(11a)groups.

Embodiment XXXIII

The compound of Embodiment XXX, or a pharmaceutically acceptable salt orsolvate thereof, wherein R^(4d) is alkyl, arylalkyl, or aryl, any ofwhich is optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, alkyl,halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein the aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl are optionally substituted with 1, 2, or 3 independentlyselected R^(11a) groups; and R^(4e) is hydrogen.

Embodiment XXXIV

The compound of any one of Embodiments I-XXII, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(4a1) is —N(H)SO₂R^(4f)

Embodiment XXXV

The compound of Embodiment XXXIV, or a pharmaceutically acceptable saltor solvate thereof, wherein R^(4f) is alkyl or aryl, wherein the aryl isoptionally substituted with 1, 2, or 3 independently selected R^(11a)groups.

Embodiment XXXVI

The compound of any one of Embodiments I-XXII, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(4a1) is:

Embodiment XXXVII

The compound of Embodiment XXXVI, or a pharmaceutically acceptable saltor solvate thereof, wherein R^(5a) and R^(5b) are each hydrogen.

Embodiment XXXVIII

The compound of Embodiment XXXVI or XXXVII, or a pharmaceuticallyacceptable salt or solvate thereof, wherein n is 1.

Embodiment XXXIX

The compound of any one of Embodiments XXXVI-XXXVIII, or apharmaceutically acceptable salt or solvate thereof, wherein R⁶ isselected from the group consisting of hydrogen and C₁₋₄ alkyl.

Embodiment XL

The compound of Embodiment XXXIX, or a pharmaceutically acceptable saltor solvate thereof, wherein R⁶ is hydrogen.

Embodiment XLI

The compound of any one of Embodiments I-XXII, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(4a1) is:

Embodiment XLII

The compound of Embodiment XLI, or a pharmaceutically acceptable salt orsolvate thereof, wherein R^(5c) and R^(5d) are each hydrogen.

Embodiment XLIII

The compound of Embodiment XLI or XLII, or a pharmaceutically acceptablesalt or solvate thereof, wherein o is 1.

Embodiment XLIV

The compound of any one of Embodiments XLI-XLIII, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(8b) is hydrogen.

Embodiment XLV

The compound of Embodiment XLI, or a pharmaceutically acceptable salt orsolvate thereof, wherein R^(4a) is:

Embodiment XLVI

The compound of Embodiment XLI, or a pharmaceutically acceptable salt orsolvate thereof, wherein R^(4a) is:

Embodiment XLVII

The compound of any one of Embodiments XLI-XLVI, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(8a) is hydrogen or C₁₋₄alkyl, wherein the alkyl is optionally substituted with 1 or 2substituents, each independently selected from the group consisting ofhydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy,alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein the aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl are optionally substituted with 1, 2, or 3 independentlyselected R^(11a) groups.

Embodiment XLVIII

The compound of any one of Embodiments XLI-XLVII, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R⁷ is hydrogen.

Embodiment XLIX

The compound of any one of Embodiments XLI-XLVI, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R⁷ and R^(8a) taken togetherwith the atoms to which they are attached form a 5-membered heterocyclo.

Embodiment L

The compound of any one of Embodiments XLI-XLIX, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R⁹ is hydrogen.

Embodiment LI

The compound of Embodiment XLI, wherein R^(4a1) is selected from thegroup consisting of:

Embodiment LII

The compound of any one of Embodiments I-XXII, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(4a1) is:

Embodiment LIII

The compound of Embodiment LII, or a pharmaceutically acceptable salt orsolvate thereof, wherein R^(5e) and R^(5f) are each hydrogen.

Embodiment LIV

The compound of Embodiments LII or LIII, or a pharmaceuticallyacceptable salt or solvate thereof, wherein p is 1.

Embodiment LV

The compound of any one of Embodiments LII-LIV, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R¹⁰ is hydrogen, or alkyl,cycloalkyl, aryl, heteroaryl, or arylalkyl, any of which is optionallysubstituted with 1, 2, or 3 substituents, each independently selectedfrom the group consisting of hydroxy, alkyl, halo, haloalkyl, amino,alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionallysubstituted with 1, 2, or 3 independently selected R^(11a) groups.

Embodiment LVI

The compound of Embodiment LV, or a pharmaceutically acceptable salt orsolvate thereof, wherein R¹⁰ is hydrogen

Embodiment LVII

The compound of Embodiment LV, or a pharmaceutically acceptable salt orsolvate thereof, wherein R¹⁰ is selected from the group consisting of:

Embodiment LVIII

The compound of any one of Embodiments I-LVII, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(4b1) is hydrogen.

Embodiment LIX

The compound of any one of Embodiments I-LVII, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(4b1) is:

Embodiment LX

The compound of Embodiment IV having the Formula XIV:

and the pharmaceutically acceptable salts and solvates thereof, whereinR is hydrogen, alkyl, or cycloalkyl.

Embodiment LXI

The compound of Embodiment I having the Formula XV:

and the pharmaceutically acceptable salts and solvates thereof.

Embodiment LXII

The compound of Embodiment I having the Formula XVI:

and the pharmaceutically acceptable salts and solvates thereof.

Embodiment LXIII

The compound of Embodiments LXI or LXII, wherein R¹ is selected from thegroup consisting of OH and methoxy; R² is selected from the groupconsisting of —CH₃ and —CH₂(cyclopropyl); and R³ is selected from thegroup consisting of hydrogen and OH, and the pharmaceutically acceptablesalts and solvates thereof.

Embodiment LXIV

The compound of any one of Embodiments LXI-LXIII, wherein R^(4a1) isselected from the group consisting of C₃-C₆ alkyl, (cycloalkyl)alkyl,C₃-C₆ alkoxy, aralkyloxy, —N(H)COR^(4c), —CH₂C(═O)NR^(4d)R^(4e),—N(H)SO₂R^(4f),

and the pharmaceutically acceptable salts and solvates thereof.

Embodiment LXV

The compound of Embodiment I selected from the group consisting of:

-   (4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-7-isobutoxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7S,8aS,9R)-7-(benzyloxy)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)isobutyramide;-   N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)isobutyramide;-   N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamide;-   N-((4bR,7    S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)propionamide;-   N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-4-methylpentanamide;-   N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-5-methylhexanamide;-   N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)pivalamide;-   N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-3-methylbutanamide;-   N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)cyclopropanecarboxamide;-   N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)cyclopentanecarboxamide;-   N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)benzamide;-   (S)—N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-2-methylbutanamide;-   N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)cyclohexanecarboxamide;-   N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)ethanesulfonamide;-   N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)benzenesulfonamide;-   (4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-7-(2-hydroxyethyl)-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7S,8aS,9R)-7-(2-(benzyloxy)ethyl)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-7-(2-methoxyethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7 S,8    aS,9R)-7-(2-(benzyloxy)ethyl)-8a-hydroxy-3-methoxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-hydroxyethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7    S,8aS,9R)-3-(benzyloxy)-11-(cyclopropylmethyl)-8a-hydroxy-7-(2-hydroxyethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6    (7H)-one;-   ethyl    2-((4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetate;-   2-((4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetic    acid;-   2-((4bR,7R,8    aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetic    acid;-   (4bR,8aS,9R,E)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-7-(3-methylbutylidene)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7 S,8    aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-isopentyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4 bR,7 S,    8aS,9R)-7-(cyclopentylmethyl)-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7    S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-methylbutyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7S,8aS,9R)-7-butyl-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7 S,    8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-neopentyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-isobutyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7S,8aS,9R)-7-(cyclohexylmethyl)-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7S,8aS,9R)-7-benzyl-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bS,7S,8aR,9R)-11-(cyclopropylmethyl)-7-isopropyl-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bS,7S,8aR,9R)-11-(cyclopropylmethyl)-3-hydroxy-7-isopropyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bS,7R,8aR,9R)-11-(cyclopropylmethyl)-3-hydroxy-7-isopropyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetyl)-L-alanine;-   (4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-7-(2-oxo-2-(piperidin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-7-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7R,8aS,9R)-8a-hydroxy-7-(2-(4-hydroxypiperidin-1-yl)-2-oxoethyl)-3-methoxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-7-(2-morpholino-2-oxoethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-7-(2-oxo-2-(piperidin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7R,8aS,9R)-3,8a-dihydroxy-7-(2-(4-hydroxypiperidin-1-yl)-2-oxoethyl)-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-N-isobutylacetamide;-   N-benzyl-2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamide;-   N-(cyclopropylmethyl)-2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamide;-   2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-N-(2-hydroxyethyl)acetamide;-   2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-N-(3-hydroxypropyl)acetamide;-   2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-N-(2-hydroxyethyl)acetamide;-   2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-N-(3-hydroxypropyl)acetamide;-   (4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-7-(2-oxo-2-(piperazin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-7-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7R,8aS,9R)-7-(2-(4-benzylpiperazin-1-yl)-2-oxoethyl)-3,8a-dihydroxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-7-(2-oxo-2-(4-phenylpiperazin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-oxo-2-(piperazin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7R,8aS,9R)-7-(2-(4-benzylpiperazin-1-yl)-2-oxoethyl)-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-oxo-2-(4-phenylpiperazin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamide;-   N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)propionamide;-   N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)isobutyramide;-   N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)pivalamide;-   N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-4-methylpentanamide;-   N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-5-methylhexanamide;-   N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)cyclohexanecarboxamide;-   (4bS,7    S,8aR,9R)-11-(cyclopropylmethyl)-3-hydroxy-7-isopentyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bS,7    S,8aR,9R)-7-(cyclopentylmethyl)-11-(cyclopropylmethyl)-3-hydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bR,7S,8aS,9R)-3,8a-dihydroxy-7-isopentyl-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   (4bS,7S,8aR,9R)-7-(cyclopentylmethyl)-3-hydroxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;-   N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)methanesulfonamide;-   N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)piperidine-4-carboxamide;    and-   N-((4bR,7    S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-2-(dimethylamino)acetamide,    and the pharmaceutically acceptable salts and solvates thereof.

Embodiment LXVI

The compound of Embodiment II selected from the group consisting of:

-   ethyl    2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetate;-   2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetic    acid;-   2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetic    acid;-   2,2′-((4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-7,7-diyl)diacetic    acid;-   2,2′-((4bR,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-7,7-diyl)diacetic    acid;-   (S)-2-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamido)propanoic    acid;-   (S)-2-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamido)propanoic    acid;-   (S)-1-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetyl)pyrrolidine-2-carboxylic    acid;-   (S)-1-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetyl)pyrrolidine-2-carboxylic    acid;-   (S)-2-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamido)-4-methylpentanoic    acid;-   (S)-2-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamido)-4-methylpentanoic    acid,    and the pharmaceutically acceptable salts and solvates thereof.

Embodiment LXVII

A pharmaceutical composition, comprising a compound of any one ofEmbodiments I-LXVI, or a pharmaceutically acceptable salt or solvatethereof, and one or more pharmaceutically acceptable carriers.

Embodiment LXVIII

A method of treating or preventing a disorder responsive to themodulation of one or more opioid receptors in a patient, comprisingadministering to a patient in need of such treatment or prevention aneffective amount of a compound of any one of Embodiments I-LXVI, or apharmaceutically acceptable salt or solvate thereof.

Embodiment LXIX

The method of Embodiment LXVIII, wherein the disorder is responsive tomodulation of μ-opioid receptor or the κ-opioid receptor, or tomodulation of a combination thereof.

Embodiment LXX

The method of Embodiment LXIX, wherein the disorder is responsive tomodulation of μ-opioid receptor.

Embodiment LXXI

The method of any one of Embodiments LXVIII-LXX, wherein the disorder ispain.

Embodiment LXXII

A method of treating or preventing pain, constipation, diarrhea,pruritis, an addictive disorder, withdrawal from alcohol addiction orwithdrawal from drug addiction in a patient, comprising administering aneffective amount of a compound of any one of Embodiments I-LXVI, or apharmaceutically acceptable salt or solvate thereof, to a patient inneed of such treatment or prevention.

Embodiment LXXIII

The method of Embodiment LXXII, wherein the method is for treating pain.

Embodiment LXXIV

The method of Embodiment LXXIII, wherein said pain is acute pain,chronic pain or surgical pain.

Embodiment LXXV

The method of Embodiment LXXIV, wherein said pain is chronic pain.

Embodiment LXXVI

The method of Embodiment LXXV, wherein said chronic pain is neuropathicpain, postoperative pain, or inflammatory pain.

Embodiment LXXVII

A method of modulating one or more opioid receptors in a patient,comprising administering to the patient an effective amount of acompound of any one of Embodiments I-LXVI, or a pharmaceuticallyacceptable salt or solvate thereof.

Embodiment LXXVIII

The method of Embodiment LXXVII, wherein the μ- or κ-opioid receptor ismodulated, or both the μ- and κ-opioid receptors are modulated.

Embodiment LXXIX

A compound of any one of Embodiments I-LXVI, or a pharmaceuticallyacceptable salt or solvate thereof, for use in treatment or preventionof a disorder responsive to the modulation of one or more opioidreceptors in a patient.

Embodiment LXXX

The compound of Embodiment LXXIX, wherein the disorder is responsive tomodulation of the μ-opioid receptor or the κ-opioid receptor, or tomodulation of a combination thereof.

Embodiment LXXXI

The compound of Embodiment LXXIX or LXXX, wherein the disorder isresponsive to modulation of the κ-opioid receptor.

Embodiment LXXXII

The compound of any one of Embodiments LXXIX-LXXXI, wherein the disorderis pain.

Embodiment LXXXIII

A compound of any one of Embodiments I-LXVI, or a pharmaceuticallyacceptable salt or solvate thereof, for use in treatment or preventionof pain, constipation, diarrhea, pruritis, an addictive disorder,withdrawal from alcohol addiction or withdrawal from drug addiction in apatient.

Embodiment LXXXIV

The compound of Embodiment LXXXIII, wherein said use is for thetreatment or prevention of pain.

Embodiment LXXXV

The compound of Embodiment LXXXIV, wherein said pain is acute pain,chronic pain or surgical pain.

Embodiment LXXXVI

The compound of Embodiment LXXXV, wherein said chronic pain isneuropathic pain, postoperative pain, or inflammatory pain.

Embodiment LXXXVII

A compound of any one of Embodiments I-LXVI, or a pharmaceuticallyacceptable salt or solvate thereof, for use in modulating of one or moreopioid receptors in a patient.

Embodiment LXXXVIII

The compound of Embodiment LXXXVII, wherein the μ- or κ-opioid receptoris modulated, or both the μ- and κ-opioid receptors are modulated.

Embodiment LXXXIX

Use of a compound of any one of Embodiments I-LXVI, or apharmaceutically acceptable salt or solvate thereof, in the manufactureof a medicament for treating or preventing a disorder responsive to themodulation of one or more opioid receptors.

Embodiment XC

The use of Embodiment LXXXIX, wherein the disorder is responsive tomodulation of the μ-opioid receptor or the κ-opioid receptor, or tomodulation of a combination thereof.

Embodiment XCI

The use of Embodiment XC, wherein the disorder is responsive tomodulation of the κ-opioid receptor.

Embodiment XCII

The use of any one of Embodiments LXXXIX-XCI, wherein the disorder ispain.

Embodiment XCIII

Use of a compound of any one of Embodiments I-LXVI, or apharmaceutically acceptable salt or solvate thereof, in the manufactureof a medicament for treating or preventing pain, constipation, diarrhea,pruritis, an addictive disorder, withdrawal from alcohol addiction orwithdrawal from drug addiction.

Embodiment XCIV

The use of Embodiment XCIII, wherein said use is for treating orpreventing pain.

Embodiment XCV

The use of Embodiment XCIV, wherein said pain is acute pain, chronicpain or surgical pain.

Embodiment XCVI

The use of Embodiment XCV, wherein said chronic pain is neuropathicpain, postoperative pain, or inflammatory pain

Embodiment XCVII

Use of a compound of any one of Embodiments I-LXVI, or apharmaceutically acceptable salt or solvate thereof, in the manufactureof a medicament for modulating of one or more opioid receptor.

Embodiment XCVIII

The use of Embodiment XCVII, wherein the μ- or κ-opioid receptor ismodulated, or both the μ- and κ-opioid receptors are modulated.

Embodiment XCIX

A compound of any one of Embodiments I-LXVI, or a pharmaceuticallyacceptable salt or solvate thereof, for use as a medicament.

Embodiment C

A compound of any one of Embodiments I-LXVI, or a pharmaceuticallyacceptable salt or solvate, wherein the compound is ³H, ¹¹C, or ¹⁴Cradiolabeled.

Embodiment CI

A method of screening a candidate compound for the ability to bind to anopioid receptor using a radiolabeled compound of Embodiment C,comprising a) introducing a fixed concentration of the radiolabeledcompound to the receptor to form a complex; b) titrating the complexwith a candidate compound; and c) determining the binding of thecandidate compound to said receptor.

Embodiment CII

A method of preparing a pharmaceutical composition, comprising admixinga therapeutically effective amount of a compound of any one ofEmbodiments I-LXVI, or a pharmaceutically acceptable salt or solvatethereof, with a pharmaceutically acceptable carrier.

Embodiment CIII

A kit, comprising a sterile container containing an effective amount ofa compound of any one of Embodiments I-LXVI, or a pharmaceuticallyacceptable salt or solvate thereof, and instructions for therapeuticuse.

Suitable hydroxyl protecting groups for PG are well known and include,for example, any suitable hydroxyl protecting group disclosed in Wuts,P. G. M. & Greene, T. W., Greene's Protective Groups in OrganicSynthesis, 4rd Ed., pp. 16-430 (J. Wiley & Sons, 2007), hereinincorporated by reference in its entirety. The term “hydroxyl protectinggroup” as used herein refers to a group that blocks (i.e., protects) thehydroxy functionality while reactions are carried out on otherfunctional groups or parts of the molecule. Those skilled in the artwill be familiar with the selection, attachment, and cleavage ofprotecting groups and will appreciate that many different protectivegroups are known in the art, the suitability of one protective group oranother being dependent on the particular synthetic scheme planned.Suitable hydroxy protecting groups are generally able to be selectivelyintroduced and removed using mild reaction conditions that do notinterfere with other portions of the subject compounds. These protectinggroups can be introduced or removed at a convenient stage using methodsknown in the art. The chemical properties of such groups, methods fortheir introduction and removal are known in the art and can be found,for example, in Greene, T. W. and Wuts, P. G. M., above. Additionalhydroxyl protecting groups can be found, for example, in U.S. Pat. No.5,952,495, U.S. Patent Appl. Pub. No. 2008/0312411, WO 2006/035195, andWO 98/02033, which are herein incorporated in their entireties. Suitablehydroxyl protecting groups include the methoxymethyl, tetrahydropyranyl,tert-butyl, allyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,acetyl, pivaloyl, benzoyl, benzyl (Bn), and p-methoxybenzyl group.

It will be apparent to a person of ordinary skill in the art in view ofthis disclosure that certain groups included in the definitions of —O—PGoverlap with the other definitions for R¹, such as methoxy, tert-butoxy,etc., and, thus, certain Compounds of the Invention having R¹ groupsthat include groups acting as hydroxyl protecting groups can bepharmaceutically active as described herein.

In one embodiment, the hydroxyl protecting group PG is selected from thegroup consisting of alkyl, arylalkyl, heterocyclo, (heterocyclo)alkyl,acyl, silyl, and carbonate, any of which are optionally substituted.

In another embodiment, the hydroxyl protecting group PG is an alkylgroup, typically an optionally substituted C₁₋₆ alkyl group, andsuitably unsubstituted methyl or tert-butyl.

In another embodiment, the hydroxyl protecting group PG is an arylalkylgroup. Suitable arylalkyl groups include, for example, an unsubstitutedbenzyl group, substituted benzyl groups, such as p-methoxybenzyl, andnaphthylmethyl.

In another embodiment, the hydroxyl protecting group PG is a heterocyclogroup, such as unsubstituted tetrahydropyranyl or optionally substitutedtetrahydropyranyl.

In another embodiment, the hydroxyl protecting group PG is a(heterocyclo)alkyl group. Suitable (heterocyclo)alkyl groups include,for example, 4-morpholinyl(C₁₋₄)alkyl groups, such as,2-(4-morpholinyl)ethyl.

In another embodiment, the hydroxyl protecting group PG is a silylgroup. The term “silyl” as employed herein refers to the group havingthe following structure:

wherein R¹², R¹³, and R¹⁴ are each independently selected from the groupconsisting of alkyl, cycloalkyl, aryl, (cycloalkyl)alkyl, or arylalkyl,any of which is optionally substituted. In one embodiment, the silylgroup is trimethyl silyl, tert-butyldimethyl silyl, tert-butyldiphenylsilyl, or tri-isopropyl silyl.

In another embodiment, the hydroxyl protecting group PG is an acylgroup. The term “acyl” as employed herein refers to the followingstructure:

wherein R¹⁵ is alkyl, cycloalkyl, aryl, (cycloalkyl)alkyl, or arylalkyl,any of which is optionally substituted. The acyl group can be, forexample, C₁₋₄ alkylcarbonyl (such as, for example, acetyl), arylcarbonyl(such as, for example, benzoyl), levulinoyl, or pivaloyl. In anotherembodiment, the acyl group is benzoyl.

In another embodiment, the hydroxyl protecting group is a carbonategroup. The term “carbonate” as employed herein refers to the followingstructure:

wherein R¹⁶ is alkyl, alkenyl, cycloalkyl, aryl, (cycloalkyl)alkyl, orarylalkyl, any of which is optionally substituted. Typically, R¹⁶ isC₁₋₁₀ alkyl (e.g., 2,4-dimethylpent-3-yl), C₂₋₆ alkenyl (e.g., ethenylor prop-2-enyl, i.e., allyl), C₃₋₁₂ cycloalkyl (e.g., adamantyl),phenyl, or benzyl.

In another embodiment, the present disclosure provides a pharmaceuticalcomposition comprising a Compound of the Invention and one or morepharmaceutically acceptable carriers.

In another embodiment, the present disclosure provides a pharmaceuticalcomposition comprising a Compound of the Invention in a therapeuticallyeffective amount and one or more pharmaceutically acceptable carriers.

In another embodiment, the present disclosure provides a method oftreating or preventing a disorder responsive to the modulation of one ormore opioid receptors in a patient, comprising administering to apatient in need of such treatment or prevention an effective amount of aCompound of the Invention. In another embodiment, the disorder isresponsive to modulation of the μ-opioid receptor or the κ-opioidreceptor, or to modulation of a combination thereof. In anotherembodiment, the disorder is responsive to modulation of the κ-opioidreceptor. In another embodiment, the disorder is pain.

In another embodiment, the present disclosure provides a method oftreating or preventing pain, constipation, diarrhea, pruritis, anaddictive disorder, withdrawal from alcohol addiction or withdrawal fromdrug addiction in a patient, comprising administering an effectiveamount of a Compound of the Invention to a patient in need of suchtreatment or prevention. In another embodiment, the method is fortreating pain. In another embodiment, the pain is acute pain, chronicpain or surgical pain. In another embodiment, the pain is chronic pain.In another embodiment, the chronic pain is neuropathic pain,postoperative pain, or inflammatory pain.

In another embodiment, the present disclosure provides a method ofmodulating one or more opioid receptors in a patient, comprisingadministering to the patient an effective amount of Compound of theInvention. In another embodiment, the μ- or κ-opioid receptor ismodulated, or both the μ- and κ-opioid receptors are modulated.

In another embodiment, the present disclosure provides a Compound of theInvention for use in treatment or prevention of a disorder responsive tothe modulation of one or more opioid receptors in a patient. In anotherembodiment, the disorder is responsive to modulation of the μ-opioidreceptor or the κ-opioid receptor, or to modulation of a combinationthereof. In another embodiment, the disorder is responsive to modulationof the κ-opioid receptor. In another embodiment, the disorder is pain.

In another embodiment, the present disclosure provides a Compound of theInvention for use in treatment or prevention of pain, constipation,diarrhea, pruritis, an addictive disorder, withdrawal from alcoholaddiction or withdrawal from drug addiction in a patient. In anotherembodiment, the use is for the treatment or prevention of pain. Inanother embodiment, the pain is acute pain, chronic pain or surgicalpain. In another embodiment, the chronic pain is neuropathic pain,postoperative pain, or inflammatory pain. In another embodiment, thepresent disclosure provides a Compound of the Invention for use inmodulating of one or more opioid receptors in a patient. In anotherembodiment, the μ- or κ-opioid receptor is modulated, or both the μ- andκ-opioid receptors are modulated.

In another embodiment, the present disclosure provides the use of aCompound of the Invention in the manufacture of a medicament fortreating or preventing a disorder responsive to the modulation of one ormore opioid receptors. In another embodiment, the disorder is responsiveto modulation of the μ-opioid receptor or the κ-opioid receptor, or tomodulation of a combination thereof. In another embodiment, the disorderis responsive to modulation of the κ-opioid receptor. In anotherembodiment, the disorder is pain.

In another embodiment, the present disclosure provides the use of aCompound of the Invention in the manufacture of a medicament fortreating or preventing pain, constipation, diarrhea, pruritis, anaddictive disorder, withdrawal from alcohol addiction or withdrawal fromdrug addiction. In another embodiment, the use is for treating orpreventing pain. In another embodiment, the pain is acute pain, chronicpain or surgical pain. In another embodiment, the chronic pain isneuropathic pain, postoperative pain, or inflammatory pain.

In another embodiment, the present disclosure provides the use of aCompound of the Invention in the manufacture of a medicament formodulating of one or more opioid receptors. In another embodiment, theμ- or κ-opioid receptor is modulated, or both the μ- and κ-opioidreceptors are modulated.

In another embodiment, the present disclosure provides a Compound of theInvention for use as a medicament.

In another embodiment, the present disclosure provides a ³H, ¹¹C, or ¹⁴Cradiolabeled Compound of the Invention.

In another embodiment, the present disclosure provides a method ofscreening a candidate compound for the ability to bind to an opioidreceptor using a radiolabeled Compound of the Invention, comprising a)introducing a fixed concentration of the radiolabeled compound to thereceptor to form a complex; b) titrating the complex with a candidatecompound; and c) determining the binding of the candidate compound tosaid receptor.

In another embodiment, the present disclosure provides a method ofpreparing a pharmaceutical composition, comprising admixing atherapeutically effective amount of a Compound of the Invention with apharmaceutically acceptable carrier.

In another embodiment, the present disclosure provides a kit, comprisinga sterile container containing an effective amount of a Compound of theInvention and instructions for therapeutic use.

Optional substituents attached to aryl, phenyl and heteroaryl rings eachtake the place of a hydrogen atom that would otherwise be present in anyposition on the aryl, phenyl or heteroaryl rings.

Useful halo or halogen groups include fluorine, chlorine, bromine andiodine.

Useful alkyl groups are selected from straight-chain and branched-chainC₁₋₁₀ alkyl groups. Typical C₁₋₁₀ alkyl groups include methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, andn-decyl, isopropyl, sec-butyl, tert-butyl, iso-butyl, iso-pentyl,neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimethylhexyl,1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl,1,3-dimethylheptyl, and 3,3-dimethylheptyl, among others. In oneembodiment, useful alkyl groups are selected from straight chain C₁₋₆alkyl groups and branched chain C₃₋₆ alkyl groups. Typical C₁₋₆ alkylgroups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, iso-butyl, pentyl, 3-pentyl, hexyl, among others. In oneembodiment, useful alkyl groups are selected from straight chain C₂₋₆alkyl groups and branched chain C₃₋₆ alkyl groups. Typical C₂₋₆ alkylgroups include ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,iso-butyl, pentyl, 3-pentyl, hexyl among others. In one embodiment,useful alkyl groups are selected from straight chain C₁₋₄ alkyl groupsand branched chain C₃₋₄ alkyl groups.

Typical C₁₋₄ alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, tert-butyl, and iso-butyl.

Useful alkenyl groups are selected from straight-chain andbranched-chain C₂₋₆ alkenyl groups, preferably C₂₋₄ alkenyl. TypicalC₂₋₆ alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl,sec-butenyl, pentenyl, and hexenyl. Typical C₂₋₄ alkenyl groups includeethenyl, propenyl, isopropenyl, butenyl, and sec-butenyl.

Useful alkynyl groups are selected from straight-chain andbranched-chain C₂₋₄ alkynyl groups, preferably C₂₋₄ alkynyl. TypicalC₂₋₆ alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl,pentynyl, and hexynyl groups. Typical C₂₋₄ alkynyl groups includeethynyl, propynyl, butynyl, and 2-butynyl groups.

Useful haloalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups, and preferably C₁₋₆ alkyl groups, and preferably any of theabove-mentioned C₁₋₄ alkyl groups, substituted by one or more fluorine,chlorine, bromine or iodine atoms (e.g., fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, andtrichloromethyl groups).

Useful hydroxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups, and preferably any of the above-mentioned C₁₋₆ alkylgroups, and preferably any of the above-mentioned C₁₋₄ alkyl groups,substituted by one or more hydroxy groups, such as monohydroxyalkyl anddihydroxyalkyl groups (e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl, hydroxypentyl, and hydroxyhexyl groups groups, andespecially hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,1,2-dihydroxyethyl, 2-hydroxypropyl, 2-hydroxyprop-2-yl,3-hydroxypropyl, 2,3-dihydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl,2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl).

Useful cycloalkyl groups are selected from saturated cyclic hydrocarbongroups containing 1, 2, or 3 rings having 3, 4, 5, 6, 7, 8, 9, 10, 11,or 12 carbon atoms (i.e., C₃-C₁₂ cycloalkyl) or the number of carbonsdesignated. In one embodiment, the cycloalkyl has one or two rings. Inanother embodiment, the cycloalkyl is a C₃-C₈ cycloalkyl. In anotherembodiment, the cycloalkyl is a C₃₋₇ cycloalkyl. In another embodiment,the cycloalkyl is a C₃₋₆ cycloalkyl. Exemplary cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, norbornyl, decalin, and adamantyl.

Useful cycloalkenyl groups are selected from partially unsaturated(i.e., containing, e.g., one or two double bonds) cyclic hydrocarbongroups containing 1, 2, or 3 rings having 4, 5, 6, 7, 8, 9, 10, 11, or12 carbon atoms (i.e., C₄-C₁₂ cycloalkenyl) or the number of carbonsdesignated. In one embodiment, the cycloalkenyl has one or two rings. Inanother embodiment, the cycloalkenyl is a C₃-C₈ cycloalkenyl. In anotherembodiment, the cycloalkenyl is a C₃₋₇ cycloalkenyl. In anotherembodiment, the cycloalkenyl is a C₃₋₆ cycloalkenyl. In one embodiment,the cycloalkenyl group contains one double bond. Exemplary cycloalkenylgroups containing one double bond include cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, andcyclodecenyl. In another embodiment, the cycloalkenyl group contains twodouble bonds. Preferably, the cycloalkenyl groups containing two doublebonds have 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (i.e., C₅-C₁₂cycloalkadienyl). Exemplary cycloalkenyl groups having two double bondsinclude cyclopentadienyl, cyclohexadienyl, cycloheptadienyl,cyclooctadienyl, cyclononadienyl, and cyclodecadienyl.

Useful alkoxy groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above (e.g., methoxy, ethoxy, propoxy,iso-propoxy, butoxy, tert-butoxy, iso-butoxy, sec-butoxy, pentyloxy,hexyloxy, heptyloxy, octyloxy, nonyloxy and decyloxy), preferably by oneof the C₁₋₆ alkyl groups, and preferably by one of the C₁₋₄ alkylgroups.

Useful alkenyloxy groups include oxygen substituted by one of the C₂₋₆alkenyl groups, and preferably by one of the C₂₋₄ alkenyl groups,mentioned above (e.g., ethenyloxy, propenyloxy, isopropenyloxy,butenyloxy, sec-butenyloxy, pentenyloxy, and hexenyloxy).

Useful alkynyloxy groups include oxygen substituted by one of the C₂₋₆alkynyl groups, preferably by one of the C₂₋₄ alkynyl groups, mentionedabove (e.g., ethynyloxy, propynyloxy, butynyloxy, 2-butynyloxy,pentynyloxy, and hexynyloxy).

Useful alkoxyalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups, and preferably any of the above-mentioned C₁₋₆ alkyl groups,substituted with any of the above-mentioned alkoxy groups (e.g.,methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl,2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, propoxymethyl,iso-propoxymethyl, 2-propoxyethyl, 3-propoxypropyl, butoxymethyl,tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, andpentyloxymethyl).

Useful haloalkoxy groups include oxygen substituted by one of the C₁₋₁₀haloalkyl groups, and preferably one of the C₁₋₆ haloalkyl groups,mentioned above (e.g., fluoromethoxy, difluoromethoxy, trifluoromethoxy,and 2,2,2-trifluoroethoxy).

Useful (cycloalkyl)alkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups, and preferably any of the above-mentioned C₁₋₆ alkylgroups, substituted with any of the above-mentioned cycloalkyl groups(e.g., (cyclopropyl)methyl, 2-(cyclopropyl)ethyl, (cyclopropyl)propyl,(cyclobutyl)methyl, (cyclopentyl)methyl, and (cyclohexyl)methyl).

Useful (cycloalkenyl)alkyl groups include any of the above-mentionedC₁₋₁₀ alkyl groups, and preferably any of the above-mentioned C₁₋₆ alkylgroups, substituted with any of the above-mentioned cycloalkenyl groups(e.g., (cyclobutenyl)methyl, 2-(cyclobutenyl)ethyl,(cyclobutenyl)propyl, (cyclopentenyl)methyl, (cyclohexenyl)methyl, and(cyclopentadienyl)methyl).

Useful aryl groups are C₆₋₁₄ aryl, especially C₆₋₁₀ aryl. Typical C₆₋₁₄aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl,azulenyl, biphenyl, biphenylenyl, and fluorenyl groups, more preferablyphenyl, naphthyl, and biphenyl groups.

Useful aryloxy groups include oxygen substituted by one of the arylgroups mentioned above (e.g., phenoxy).

Useful arylalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups, and preferably any of the above-mentioned C₁₋₆ alkyl groups,substituted by any of the above-mentioned aryl groups (e.g., benzyl andphenethyl).

Useful arylalkenyl groups include any of the above-mentioned C₂₋₆alkenyl groups substituted by any of the above-mentioned aryl groups(e.g., phenylethenyl).

Useful arylalkynyl groups include any of the above-mentioned C₂₋₆alkynyl groups substituted by any of the above-mentioned aryl groups(e.g., phenylethynyl).

Useful aralkyloxy or arylalkoxy groups include oxygen substituted by oneof the above-mentioned arylalkyl groups (e.g., benzyloxy).

Useful (arylalkoxy)carbonyl groups include a carbonyl group substitutedby any of the above-mentioned arylalkoxy groups (e.g.,(benzyloxy)carbonyl).

The term “heteroaryl” or “heteroaromatic” as employed herein refers togroups having 5 to 14 ring atoms, with 6, 10 or 14 n electrons shared ina cyclic array, and containing carbon atoms and 1, 2, or 3 oxygen,nitrogen or sulfur heteroatoms, or 4 nitrogen atoms. In one embodiment,the heteroaryl group is a 5- to 10-membered heteroaryl group. Examplesof heteroaryl groups include thienyl, benzo[b]thienyl,naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl,isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl,quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl,phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl,thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, andphenoxazinyl. Typical heteroaryl groups include thienyl (e.g.,thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl(e.g., pyrrol-1-yl, 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl(e.g., imidazol-1-yl, 1H-imidazol-2-yl and 1H-imidazol-4-yl), tetrazolyl(e.g., tetrazol-1-yl and tetrazol-5-yl), pyrazolyl (e.g.,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g.,pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g.,pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-5-yl),thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl),isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, andisothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, andoxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, andisoxazol-5-yl). A 5-membered heteroaryl can contain up to 4 heteroatoms.A 6-membered heteroaryl can contain up to 3 heteroatoms. Each heteroatomis independently selected from nitrogen, oxygen and sulfur.

Useful heteroarylalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned heteroaryl groups(e.g., (thien-2-yl)methyl, 2-furylmethyl, (pyrrol-1-yl)methyl, and2-(1H-pyrrol-2-yl)ethyl).

Useful heteroarylalkoxy groups include oxygen substituted by one of theabove-mentioned heteroaryl groups.

Useful (heteroarylalkoxy)carbonyl groups include a carbonyl groupsubstituted by any of the above-mentioned heteroarylalkoxy groups.

The terms “heterocyclic” and “heterocyclo” are used herein to meansaturated or partially unsaturated 3-7 membered monocyclic, or 7-10membered bicyclic ring system, which consist of carbon atoms and fromone to four heteroatoms independently selected from the group consistingof O, N, and S, wherein the nitrogen and sulfur heteroatoms can beoptionally oxidized, the nitrogen can be optionally quaternized, andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring, and wherein theheterocyclic ring can be substituted on a carbon atom or on a nitrogenatom if the resulting compound is stable. In one embodiment, the 3- to7-membered monocyclic heterocyclic ring is either a saturated, orunsaturated non-aromatic ring. A 3-membered heterocyclo can contain upto 1 heteroatom, a 4-membered heterocyclo can contain up to 2heteroatoms, a 5-membered heterocyclo can contain up to 4 heteroatoms, a6-membered heterocyclo can contain up to 4 heteroatoms, and a 7-memberedheterocyclo can contain up to 5 heteroatoms. Each heteroatom isindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The 3- to 7-memberedheterocyclo can be attached via a nitrogen or carbon atom. A 7- to10-membered bicyclic heterocyclo contains from 1 to 4 heteroatomsindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The 7- to 10-memberedbicyclic heterocyclo can be attached via a nitrogen or carbon atom.Examples of the heterocyclic rings include, but are not limited to,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolinyl,pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, 2-oxooxazolidinyl,tetrahydrothienyl, imidazolidinyl, hexahydropyrimidinyl, andbenzodiazepines.

Useful (heterocyclo)alkyl groups include any of the above-mentionedC₁₋₁₀ alkyl groups, and preferably any of the above-mentioned C₁₋₆ alkylgroups, substituted by any of the above-mentioned heterocyclic groups(e.g., (pyrrolidin-2-yl)methyl, (pyrrolidin-1-yl)methyl,(piperidin-1-yl)methyl, (morpholin-4-yl)methyl,(2-oxooxazolidin-4-yl)methyl, 2-(2-oxooxazolidin-4-yl)ethyl,(2-oxo-imidazolidin-1-yl)methyl, (2-oxo-imidazolidin-1-yl)ethyl, and(2-oxo-imidazolidin-1-yl)propyl).

As used herein, the term “amino” or “amino group” refers to —NH₂.

Useful aminoalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups, and preferably any of the above-mentioned C₁₋₆ alkyl groups,substituted with one or more amino group.

Useful alkylamino and dialkylamino groups are —NHR¹⁷ and —NR¹⁷R¹⁸,respectively, wherein R¹⁷ and R¹⁸ are each independently selected from aC₁₋₁₀ alkyl group.

As used herein, the term “aminocarbonyl” refers to —C(═O)NH₂.

Useful alkylcarbonyl groups include a carbonyl group, i.e., —C(═O)—,substituted by any of the above-mentioned C₁₋₁₀ alkyl groups.

Useful alkoxycarbonyl groups include a carbonyl group substituted by anyof the above-mentioned alkoxy groups (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, iso-butoxycarbonyl, sec-butoxycarbonyl, andpentyloxycarbonyl).

Useful arylcarbonyl groups include a carbonyl group substituted by anyof the above-mentioned aryl groups (e.g., benzoyl).

Useful alkylcarbonyloxy or acyloxy groups include oxygen substituted byone of the above-mentioned alkylcarbonyl groups.

Useful alkylcarbonylamino or acylamino groups include any of theabove-mentioned alkylcarbonyl groups attached to an amino nitrogen, suchas methylcarbonylamino.

As used herein, the term “carboxamido” refers to a radical of formula—C(═O)NR¹⁹R²⁰, wherein R¹⁹ and R²⁰ are each independently hydrogen,optionally substituted C₁₋₁₀ alkyl, or optionally substituted aryl.Exemplary carboxamido groups include —CONH₂, —CON(H)CH₃, —CON(CH₃)₂, and—CON(H)Ph.

Useful alkylaminocarbonyl and dialkylaminocarbonyl groups are any of theabove-mentioned carboxamido groups, where R¹⁹ is H and R²⁰ is C₁₋₁₀alkyl or where R¹⁹ and R²⁰ are each independently selected from a C₁₋₁₀alkyl group, respectively.

As used herein, the term “sulfonamido” refers to a radical of formula—SO₂NR²¹R²², wherein R²¹ and R²² are each independently hydrogen,optionally substituted C₁₋₁₀ alkyl, or optionally substituted aryl.Exemplary sulfonamido groups include —SO₂NH₂, —SO₂N(H)CH₃, and—SO₂N(H)Ph.

As used herein, the term “thiol” refers to —SH.

Useful mercaptoalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups, and preferably any of the above-mentioned C₁₋₆ alkylgroups, substituted by a —SH group.

As used herein, the term “carboxy” refers to —COOH.

Useful carboxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups, and preferably any of the above-mentioned C₁₋₆ alkylgroups, substituted by —COOH.

As used herein, the terms “hydroxyl” or “hydroxy” refer to —OH.

As used herein, the term “cyano” refers to —CN.

Useful cyanoalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups, and preferably any of the above-mentioned C₁₋₆ alkyl groups,substituted by a CN group. Exemplary cyanoalkyl groups include —CH₂CN,—CH₂CH₂CN, and —CH₂CH₂CH₂CN.

As used herein, the term “nitro” refers to —NO₂.

As used herein, the term “ureido” refers to —NH—C(═O)—NH₂.

As used herein, the term “azido” refers to —N₃.

The term “ambient temperature” as used herein means the temperature ofthe surroundings. The ambient temperature indoors is the same as roomtemperature, which is from about 20° C. to about 25° C.

The term “about,” as used herein in connection with a measured quantity,refers to the normal variations in that measured quantity, as expectedby the skilled artisan making the measurement and exercising a level ofcare commensurate with the objective of measurement and the precision ofthe measuring equipment. Typically, the term “about” includes therecited number±10%. Thus, “about 10” means 9 to 11.

As used herein, the term “optionally substituted” refers to a group thatmay be unsubstituted or substituted.

Optional substituents on optionally substituted groups, when nototherwise indicated, include one or more groups, typically 1, 2, or 3groups, independently selected from the group consisting of halo,halo(C₁₋₆)alkyl, aryl, heterocycle, cycloalkyl, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl(C₁₋₆)alkyl, aryl(C₂₋₆)alkenyl,aryl(C₂₋₆)alkynyl, cycloalkyl(C₁₋₆)alkyl, heterocyclo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, carboxy(C₁₋₆)alkyl,alkoxy(C₁₋₆)alkyl, nitro, amino, ureido, cyano, alkylcarbonylamino,hydroxy, thiol, alkylcarbonyloxy, aryloxy, ar(C₁₋₆)alkyloxy,carboxamido, sulfonamido, azido, C₁₋₆ alkoxy, halo(C₁₋₆)alkoxy, carboxy,aminocarbonyl, (═O), and mercapto(C₁₋₆)alkyl groups mentioned above.Preferred optional substituents include halo, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, hydroxy, nitro, C₁₋₆ alkyl, C₁₋₆alkoxy, halo(C₁₋₆)alkoxy, and amino.

Compounds of the Invention encompass all the salts of the disclosedcompounds of Formulae I-XIII, I-A-XIII-A, and XIV-XVI. The presentinvention preferably includes all non-toxic pharmaceutically acceptablesalts thereof of the disclosed compounds. Examples of pharmaceuticallyacceptable addition salts include inorganic and organic acid additionsalts and basic salts. The pharmaceutically acceptable salts include,but are not limited to, metal salts such as sodium salt, potassium salt,cesium salt and the like; alkaline earth metals such as calcium salt,magnesium salt and the like; organic amine salts such as triethylaminesalt, pyridine salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and thelike; inorganic acid salts such as hydrochloride, hydrobromide,phosphate, sulphate and the like; organic acid salts such as citrate,lactate, tartrate, maleate, fumarate, mandelate, acetate,dichloroacetate, trifluoroacetate, oxalate, formate and the like;sulfonates such as methanesulfonate, benzenesulfonate,p-toluenesulfonate and the like; and amino acid salts such as arginate,asparginate, glutamate and the like.

Acid addition salts can be formed by mixing a solution of the particularcompound of the present invention with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or thelike. Basic salts can be formed by mixing a solution of the compound ofthe present invention with a solution of a pharmaceutically acceptablenon-toxic base such as sodium hydroxide, potassium hydroxide, cholinehydroxide, sodium carbonate and the like.

Compounds of the Invention also encompass solvates of any of thedisclosed compounds of Formulae I-XIII, I-A-XIII-A, and XIV-XVI.Solvates typically do not significantly alter the physiological activityor toxicity of the compounds, and as such may function aspharmacological equivalents. The term “solvate” as used herein is acombination, physical association and/or solvation of a compound of thepresent invention with a solvent molecule such as, e.g., a disolvate,monosolvate or hemisolvate, where the ratio of solvent molecule tocompound of the present invention is about 2:1, about 1:1 or about 1:2,respectively. This physical association involves varying degrees ofionic and covalent bonding, including hydrogen bonding. In certaininstances, the solvate can be isolated, such as when one or more solventmolecules are incorporated into the crystal lattice of a crystallinesolid. Thus, “solvate” encompasses both solution-phase and isolatablesolvates. Compounds of the Invention may be present as solvated formswith a pharmaceutically acceptable solvent, such as water, methanol,ethanol, and the like, and it is intended that the invention includesboth solvated and unsolvated forms of compounds of any of FormulaeI-XIII, I-A-XIII-A, and XIV-XVI. One type of solvate is a hydrate. A“hydrate” relates to a particular subgroup of solvates where the solventmolecule is water. Solvates typically can function as pharmacologicalequivalents. Preparation of solvates is known in the art. See, forexample, M. Caira et al., J. Pharmaceut. Sci., 93(3):601-611 (2004),which describes the preparation of solvates of fluconazole with ethylacetate and with water. Similar preparation of solvates, hemisolvates,hydrates, and the like are described by E. C. van Tonder et al., AAPSPharm. Sci. Tech., 5(1):Article 12 (2004), and A. L. Bingham et al.,Chem. Commun.: 603-604 (2001). A typical, non-limiting, process ofpreparing a solvate would involve dissolving a compound of any ofFormulae I-XIII, I-A-XIII-A, and XIV-XVI in a desired solvent (organic,water, or a mixture thereof) at temperatures above about 20° C. to about25° C., then cooling the solution at a rate sufficient to form crystals,and isolating the crystals by known methods, e.g., filtration.Analytical techniques such as infrared spectroscopy can be used toconfirm the presence of the solvent in a crystal of the solvate.

Compounds of the Invention can be isotopically-labeled (i.e.,radio-labeled). Examples of isotopes that can be incorporated into thedisclosed compounds include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively, andpreferably ³H, ¹¹C, and ¹⁴C. Isotopically-labeled Compounds of theInvention can be prepared by methods known in the art in view of thisdisclosure. For example, tritiated Compounds of the Invention can beprepared by introducing tritium into the particular compound bycatalytic dehalogenation with tritium. This method may include reactinga suitable halogen-substituted precursor of a Compound of the Inventionwith tritium gas in the presence of an appropriate catalyst such as Pd/Cin the presence of a base. Other suitable methods for preparingtritiated compounds can be found in Filer, Isotopes in the Physical andBiomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6(1987). ¹⁴C-labeled compounds can be prepared by employing startingmaterials having a ¹⁴C carbon.

Isotopically labeled Compounds of the Invention, as well as thepharmaceutically acceptable salts and solvates thereof, can be used asradioligands to test for the binding of compounds to an opioid receptor.For example, a radio-labeled Compound of the Invention can be used tocharacterize specific binding of a test or candidate compound to thereceptor. Binding assays utilizing such radio-labeled compounds canprovide an in vitro alternative to animal testing for the evaluation ofchemical structure-activity relationships. For example, the receptorassay may be performed at a fixed concentration of a radiolabeledCompound of the Invention and at increasing concentrations of a testcompound in a competition assay. In a non-limiting embodiment, thepresent invention provides a method for screening a candidate compoundfor the ability to bind to an opioid receptor, comprising a) introducinga fixed concentration of a radio-labeled Compound of the Invention tothe receptor under conditions that permit binding of the radio-labeledcompound to the receptor to form a complex; b) titrating the complexwith a candidate compound; and c) determining the binding of thecandidate compound to said receptor.

Some of the compounds disclosed herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms, such as epimers. The present inventionis meant to encompass the uses of all such possible forms, as well astheir racemic and resolved forms and mixtures thereof. The individualenantiomers may be separated according to methods known to those ofordinary skill in the art in view of the present disclosure. When thecompounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that they include both E and Z geometric isomers. All tautomersare intended to be encompassed by the present invention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “epimer” refers to diastereomers that have oppositeconfiguration at only one of two or more tetrahedral streogenic centrespresent in the respective molecular entities.

The term “stereogenic center” is an atom, bearing groups such that aninterchanging of any two groups leads to a stereoisomer.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

The term “treating” or “treatment” refers to administering a therapy inan amount, manner, or mode effective to improve a condition, symptom, orparameter associated with a disorder or to prevent progression of adisorder, to either a statistically significant degree or to a degreedetectable to one skilled in the art. An effective amount, manner, ormode can vary depending on the subject and may be tailored to thepatient.

Open terms such as “include,” “including,” “contain,” “containing” andthe like mean “comprising.”

As used herein, compounds that bind to receptors and mimic theregulatory effects of endogenous ligands are defined as “agonists”.Compounds that bind to receptors and are only partly effective asagonists are defined as “partial agonists”. Compounds that bind to areceptor but produce no regulatory effect, but rather block the bindingof ligands to the receptor are defined as “antagonists”. (Ross andKenakin, “Ch. 2: Pharmacodynamics: Mechanisms of Drug Action and theRelationship Between Drug Concentration and Effect”, pp. 31-32, inGoodman & Gilman's the Pharmacological Basis of Therapeutics, 10th Ed.(J. G. Hardman, L. E. Limbird and A. Goodman-Gilman eds., 2001)).

In certain embodiments, the Compound of the Invention is an agonist atone or more of the μ, δ and/or κ opioid receptors. In certainnon-limiting embodiments, the Compound of the Invention produces fewerside effects and/or less severe side effects than currently availableanalgesic opioid compounds when administered at doses producingequivalent levels of analgesia and/or anti-hyperalgesia. In certainembodiments, the Compound of the Invention is an agonist at ORL-1 opioidreceptor.

In certain embodiments, Compounds of the Invention can be used incombination with at least one other therapeutic agent. The othertherapeutic agent can be, but is not limited to, a μ-opioid agonist, anon-opioid analgesic, a non-steroidal anti-inflammatory agent, a Cox-IIinhibitor, an anti-emetic, a β3-adrenergic blocker, an anticonvulsant,an antidepressant, a Ca²⁺-channel blocker, an anticancer agent, or amixture thereof.

Compounds of the Invention potently bind to the μ and/or κ and/or δand/or ORL-1 opioid receptors. Compounds of the Invention can bemodulators at the μ and/or κ and/or δ and/or ORL-1 opioid receptors, andtherefore Compounds of the Invention can be used/administered to treat,ameliorate, or prevent pain.

In some embodiments, Compounds of the Invention are antagonists of oneor more opioid receptors. In another embodiment, Compounds of theInvention are antagonists of the μ and/or κ opioid receptors.

In some embodiments, Compounds of the Invention are partial agonists ofone or more opioid receptors. In another embodiment, Compounds of theInvention are partial agonists of the μ and/or κ opioid receptors.

In another embodiment, Compounds of the Invention are agonists of one ormore opioid receptors. In another embodiment, Compounds of the Inventionare agonists of the μ and/or κ opioid receptors.

In some embodiments, Compounds of the Invention have both: (i)antagonist activity at the ORL-1 receptor; and (ii) agonist activity atone or more of the μ, δ and/or κ receptors. In another embodiment,Compounds of the Invention have both: (i) antagonist activity at theORL-1 receptor; and (ii) agonist activity at the μ receptor. In anotherembodiment, Compounds of the Invention have both: (i) antagonistactivity at the μ receptor; and (ii) agonist activity at the κ receptor.In another embodiment, Compounds of the Invention have: (i) antagonistactivity at the ORL-1 receptor; (ii) antagonist activity at the μreceptor; and (iii) agonist activity at the κ receptor. In anotherembodiment, Compounds of the Invention have: (i) antagonist activity atthe μ receptor; (ii) agonist activity at the κ receptor; and (iii)antagonist activity at the δ receptor.

Compounds of the Invention that are antagonists of the t-opioid receptoror agonists of κ-opioid receptor, or both, can be used/administered totreat or ameliorate constipation. Compounds of the Invention that areagonists of μ-opioid receptor can be used/administered to treat orameliorate diarrhea.

Compounds of the Invention can be used to treat or prevent acute,chronic pain (which includes but is not limited to, neuropathic pain,postoperative pain, and inflammatory pain), or surgical pain. Examplesof pain that can be treated or prevented using a Compound of theInvention include, but are not limited to, cancer pain, neuropathicpain, labor pain, myocardial infarction pain, pancreatic pain, colicpain, post-operative pain, headache pain, muscle pain, arthritic pain,and pain associated with a periodontal disease, including gingivitis andperiodontitis.

Acute pain includes, but is not limited to, perioperative pain,postoperative pain, post-traumatic pain, acute disease related pain, andpain related to diagnostic procedures, orthopedic manipulations, andmyocardial infarction. Acute pain in the perioperative setting includespain because of pre-existing disease, the surgical procedure, e.g.,associated drains, chest or nasogastric tubes, or complications, or acombination of disease-related and procedure-related sources.

Chronic pain includes, but is not limited to, inflammatory pain,postoperative pain, cancer pain, osteoarthritis pain associated withmetastatic cancer, trigeminal neuralgia, acute herpetic and postherpeticneuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion,occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout,phantom limb pain, burn pain, and other forms of neuralgia, neuropathic,and idiopathic pain syndromes.

Compounds of the Invention can be used to treat or prevent painassociated with inflammation or with an inflammatory disease in apatient. Such pain can arise where there is an inflammation of the bodytissue which can be a local inflammatory response or a systemicinflammation. For example, a Compound of the Invention can be used totreat or prevent pain associated with inflammatory diseases including,but not limited to, organ transplant rejection; reoxygenation injuryresulting from organ transplantation (see Grupp et al., J. Mol, CellCardiol. 31:297-303 (1999)) including, but not limited to,transplantation of the heart, lung, liver, or kidney; chronicinflammatory diseases of the joints, including arthritis, rheumatoidarthritis, osteoarthritis and bone diseases associated with increasedbone resorption; inflammatory bowel diseases, such as ileitis,ulcerative colitis, Barrett's syndrome, and Crohn's disease;inflammatory lung diseases, such as asthma, adult respiratory distresssyndrome, and chronic obstructive airway disease; inflammatory diseasesof the eye, including corneal dystrophy, trachoma, onchocerciasis,uveitis, sympathetic ophthalmitis and endophthalmitis; chronicinflammatory disease of the gum, including gingivitis and periodontitis;tuberculosis; leprosy; inflammatory diseases of the kidney, includinguremic complications, glomerulonephritis and nephrosis; inflammatorydisease of the skin, including sclerodermatitis, psoriasis and eczema;inflammatory diseases of the central nervous system, including chronicdemyelinating diseases of the nervous system, multiple sclerosis,AIDS-related neurodegeneration and Alzheimer's disease, infectiousmeningitis, encephalomyelitis, Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis and viral or autoimmuneencephalitis; autoimmune diseases, including Type I and Type II diabetesmellitus; diabetic complications, including, but not limited to,diabetic cataract, glaucoma, retinopathy, nephropathy (such asmicroaluminuria and progressive diabetic nephropathy), gangrene of thefeet, atherosclerotic coronary arterial disease, peripheral arterialdisease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, jointproblems, and a skin or mucous membrane complication (such as aninfection, a shin spot, a candidal infection or necrobiosis lipoidicadiabeticorum), immune-complex vasculitis, and systemic lupuserythematosus (SLE); inflammatory disease of the heart, such ascardiomyopathy, ischemic heart disease hypercholesterolemia, andartherosclerosis; as well as various other diseases that can havesignificant inflammatory components, including preeclampsia, chronicliver failure, brain and spinal cord trauma, and cancer. Compounds ofthe Invention can also be used to treat or prevent pain associated withinflammatory disease that can, for example, be a systemic inflammationof the body, exemplified by gram-positive or gram negative shock,hemorrhagic or anaphylactic shock, or shock induced by cancerchemotherapy in response to pro-inflammatory cytokines, e.g., shockassociated with pro-inflammatory cytokines. Such shock can be induced,e.g., by a chemotherapeutic agent that is administered as a treatmentfor cancer.

Compounds of the Invention can be used to treat or prevent painassociated with nerve injury (i.e., neuropathic pain). Chronicneuropathic pain is a heterogenous disease state with an unclearetiology. In chronic pain, the pain can be mediated by multiplemechanisms. This type of pain generally arises from injury to theperipheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. The chronic pain is differentfrom acute pain in that chronic neuropathic pain patients suffer theabnormal pain sensations that can be described as spontaneous pain,continuous superficial burning and/or deep aching pain. The pain can beevoked by heat-, cold-, and mechano-hyperalgesia or by heat-, cold-, ormechano-allodynia.

Chronic neuropathic pain can be caused by injury or infection ofperipheral sensory nerves. It includes, but is not limited to pain fromperipheral nerve trauma, herpes virus infection, diabetes mellitus,causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis.Neuropathic pain can also be caused by nerve damage from chronicalcoholism, human immunodeficiency virus infection, hypothyroidism,uremia, or vitamin deficiencies. Stroke (spinal or brain) and spinalcord injury can also induce neuropathic pain. Cancer-related neuropathicpain results from tumor growth compression of adjacent nerves, brain, orspinal cord. In addition, cancer treatments, including chemotherapy andradiation therapy, can cause nerve injury. Neuropathic pain includes butis not limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

Compounds of the Invention can be used to treat or prevent painassociated with migraine including, but not limited to, migraine withoutaura (“common migraine”), migraine with aura (“classic migraine”),migraine without headache, basilar migraine, familial hemiplegicmigraine, migrainous infarction, and migraine with prolonged aura.

Compounds of the Invention can also be used as an agent to treatwithdrawal from alcohol addiction or drug addiction; as an agent totreat or prevent addictive disorders; an agent to treat a pruriticcondition; and in treating or ameliorating constipation and diarrhea.

The present invention also provides the use of a compound represented byany of defined Formulae I-XIII, I-A-XIII-A, and XIV-XVI, or apharmaceutically acceptable salt or solvate thereof, in the manufactureof a medicament for treating a disorder responsive to the modulation ofone or more opioids receptors (e.g., any of the disorders listed above)in a patient suffering from said disorder.

Furthermore, the present invention provides a method of modulating, inparticular activating, one or more opioid receptors in a patient in needthereof, said method comprising administering to the patient at leastone compound represented by any of defined Formulae I-XIII, I-A-XIII-A,and XIV-XVI, or a pharmaceutically acceptable salt or solvate thereof.

The present invention also provides the use of a compound represented byany of defined Formulae I-XIII, I-A-XIII-A, and XIV-XVI, or apharmaceutically acceptable salt or solvate thereof, in the manufactureof a medicament, in particular a medicament for modulating, inparticular activating, one or more opioid receptors, in a patient inneed thereof.

Synthesis of Compounds

Compounds of the Invention can be prepared using methods known to thoseskilled in the art in view of this disclosure, or by illustrativemethods shown in the schemes below. For example, compounds of Formula IVwherein R¹ is methoxy, R³ is hydroxy, and R^(4b) is hydrogen can beprepared as shown in Scheme 1. Additional methods of synthesis aredescribed in Schemes 2-5 and illustrated in the working examples setforth below.

Briefly, naloxone, A, is methylated by reaction with a suitable reagentsuch as methyl iodide (Mel) in a suitable solvent such asdimethylformamide (DMF) in the presence of an inorganic base such aspotassium carbonate (K₂CO₃) or an organic base such asdiisopropylethylamine to provide the methyl ether B. Compound C isprepared by deallylation of compound B with a palladium catalyst such aspalladium tetrakistriphenylphosphine (Pd(PPh₃)₄) in the presence of asuitable acid source such as dimethylbarbituric acid. Compound D isprepared by alkylation of compound C with an alkyl halide in a suitablesolvent such as acetonitrile (AcCN), dimethylformamide (DMF) or dimethylsulfoxide (DMSO) in the presence of an inorganic base such as potassiumcarbonate or an organic base such as diisopropylethylamine. Compound Dcan also be prepared by reductive amination of compound C with analdehyde or ketone using sodium cyanoborohydride or sodiumtriacetoxyborohydride in a suitable solvent such as dichloromethane(DCM). Compound E is prepared by reaction of compound D with an excessof zinc dust and aqueous ammonium chloride (NH₄Cl). Compound F isprepared by triflation of compound E in a suitable solvent such astetrahydrofuran (THF) in the presence of an inorganic base such ascesium carbonate (Cs₂CO₃). Compound G is prepared viapalladium-catalyzed aryl triflate reduction with triethylsilane. Acompound having Formula IV (wherein R^(4a) is R^(4a)-I and n is 1) isprepared by reaction of compound G with an alkyl halide or otherelectrophile in a suitable solvent such as THF or DMF in the presence ofa base such as sodium hydride or sodium hexamethyldisilazide (NaHMDS).(U.S. Pat. No. 4,423,221; Kawamura, Chem. Pharm. Bull. 52:747 (2004)).Conversion of the ester to the acid and coupling with a compound havingH(R⁷)N—C(R^(8a))(R^(8b))—CO₂R⁹, e.g., an amino acid or amino ester,provides a compound having Formula IV (wherein R^(4a) is R^(4a)-II and ois 1).

The opposite isomers of the compounds described in Scheme 1 can beprepared starting from compounds of Formula G′:

Compounds of Formula G′ can be prepared according methods described inthe art, such as, for example, in US 2009/0156818, US 2009/0156820, andHupp C. D., et al., Tetrahedron Letters 51:2359-2361 (2010).Accordingly, for example, a compound of Formula X wherein R¹ is OMe, R³is hydroxy, and R^(4b) is hydrogen can be prepared as described inScheme 2 starting from CAS #6080-33-7.

As described in Scheme 3, Compound H is prepared from Compound G byacylation followed by reaction with a sulfonyl azide such as4-acetamidobenzenesulfonyl azide in the presence of a suitable base suchas DBU in a suitable solvent such as ACN. Compound H can be converted toCompound I by reaction with a suitable alcohol in the presence of asuitable catalyst such as rhodium(II) acetate dimer in a suitablesolvent such as DCE followed by cleavage of the acetate protecting groupby treatment with a suitable base such as NaOH in aq. MeOH. Compound Hcan also be converted to Compound J by conditions similar to thepreparation of Compound I except an amide or carbamate is used insteadof an alcohol. When the carbamate contains a Boc group, Compound J canbe converted to Compound K by first cleaving the Boc group by treatmentwith a suitable acid such as TFA in a suitable solvent such as DCM,followed by reaction with a suitable sulfonyl chloride (wherein R^(x′)is, e.g., alkyl or aryl) in the presence of a suitable base such asDIPEA in a suitable solvent such as DCM.

In Scheme 4, Compound L can be prepared from a compound having FormulaIV (see Scheme 1) by reaction of the ketone group with a suitable diolsuch as ethylene glycol in the presence of an acid catalyst such as PTSAin a suitable solvent such as toluene. Treatment of Compound L with asuitable reducing agent such as DIBAL in a suitable solvent such as DCMgives Compound M. Treatment of Compound M with a suitable acid such asaq. HCl gives Compound N. Compound M can be converted to Compound O bytreatment with a suitable base such as NaH and a suitable alkylatingagent in a suitable solvent such as DMF. Treatment of Compound O with asuitable acid such as aq. HCl gives Compound P.

In Scheme 5, Compound Q can be prepared from Compound G by treatmentwith a suitable aldehyde or ketone in the presence of a suitable basesuch as NaOH in a suitable solvent such as aq. MeOH. Compound R can beprepared from Compound Q by reduction under suitable conditions such ashydrogenation over a suitable catalyst such as Pd/C in a suitablesolvent such as MeOH.

Subsequent side chain modifications can be accomplished via appropriatefunctional group manipulations known to one skilled in the art.

In Vitro Assay Protocols

μ-Opioid Receptor Binding Assay Procedures:

Radioligand dose-displacement binding assays for μ-opioid receptors used0.3 nM [³H]-diprenorphine (Perkin Elmer, Shelton, Conn.), with 5 mgmembrane protein/well in a final volume of 500 μl binding buffer (10 mMMgCl₂, 1 mM EDTA, 5% DMSO, 50 mM HEPES, pH 7.4). Reactions were carriedout in the absence or presence of increasing concentrations of unlabelednaloxone. All reactions were conducted in 96-deep well polypropyleneplates for 2 hours at room temperature. Binding reactions wereterminated by rapid filtration onto 96-well Unifilter GF/C filter plates(Perkin Elmer, Shelton, Conn.), presoaked in 0.5% polyethylenimine usinga 96-well tissue harvester (Perkin Elmer, Shelton, Conn.) followed byperforming three filtration washes with 500 μl of ice-cold bindingbuffer. Filter plates were subsequently dried at 50° C. for 2-3 hours.BetaScint scintillation cocktail (Perkin Elmer, Shelton, Conn.) wasadded (50 μl/well), and plates were counted using a Packard Top-Countfor 1 min/well. The data were analyzed using the one-site competitioncurve fitting functions in GraphPad PRISM™ v. 3.0 or higher (San Diego,Calif.), or an in-house function for one-site competition curve-fitting.

μ-Opioid Receptor Binding Data:

Generally, the lower the K_(i) value, the more effective Compounds ofthe Invention will be at treating or preventing pain or anotherCondition. In certain embodiments, Compounds of the Invention exhibit aK_(i) (nM) of about 30,000 or less, e.g., about 10,000 or less, forbinding to μ-opioid receptors. Typically, Compounds of the Inventionexhibit a K_(i) (nM) of about 1,000 or less, or about 300 or less, orabout 100 or less, or about 10 or less, or about 1 or less, or about 0.1or less.

μ-Opioid Receptor Functional Assay Procedures:

[³⁵S]GTPγS functional assays were conducted using freshly thawedμ-receptor membranes prepared from a cell line expressing recombinant μopioid receptor in a HEK-293, CHO or U-2 OS cell background or purchasedfrom a commercial source (Perkin Elmer, Shelton, Conn.; or DiscovRx,Fremont, Calif.). Assay reactions were prepared by sequentially addingthe following reagents to binding buffer (100 mM NaCl, 10 mM MgCl₂, 20mM HEPES, pH 7.4) on ice (final concentrations indicated): membraneprotein (0.026 mg/mL), saponin (10 mg/mL), GDP (3 mM) and [³⁵S]GTPγS(0.20 nM; Perkin Elmer, Shelton, Conn.). The prepared membrane solution(190 μl/well) was transferred to 96-shallow well polypropylene platescontaining 10 μl of 20× concentrated stock solutions of the agonist[D-Ala², N-methyl-Phe⁴ Gly-ol⁵]-enkephalin (DAMGO) prepared in dimethylsulfoxide (DMSO). Plates were incubated for 30 min at about 25° C. withshaking. Reactions were terminated by rapid filtration onto 96-wellUnifilter GF/B filter plates (Perkin Elmer, Shelton, Conn.) using a96-well tissue harvester (Perkin Elmer, Shelton, Conn.) followed bythree filtration washes with 200 μl of ice-cold wash buffer (10 mMNaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates were subsequently driedat 50° C. for 2-3 hours. BetaScint scintillation cocktail (Perkin Elmer,Shelton, Conn.) was added (50 μl/well) and plates were counted using aPackard Top-Count for 1 min/well. Data were analyzed using the sigmoidaldose-response curve fitting functions in GraphPad PRISM v. 3.0, or anin-house function for non-linear, sigmoidal dose-response curve-fitting.

μ-Opioid Receptor Functional Data:

μ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a μ-opioid receptor. Typically,Compounds of the Invention exhibit a μ GTP EC₅₀ (nM) of about 5,000 orless, or about 2000 or less, or about 1,000 or less, or about 100 orless, or about 10 or less, or about 1 or less, or about 0.1 or less.

μ GTP E_(max) (%) is the maximal effect elicited by a compound relativeto the effect elicited by DAMGO, a standard p agonist. Generally, the μGTP E_(max) (%) value measures the efficacy of a compound to treat orprevent pain or other Conditions. Typically, Compounds of the Inventionexhibit a μ GTP E_(max) (%) of greater than about 10%, or greater thanabout 20%, or greater than about 50%, or greater than about 65%, orgreater than about 75%, or greater than about 85%, or greater than about100%.

κ-Opiold Receptor Binding Assay Procedures:

Membranes from HEK-293 cells, CHO or U-2 OS cells expressing therecombinant human kappa opioid receptor (κc) were prepared by lysingcells in ice cold hypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES, pH 7.4)(10 mL/10 cm dish) followed by homogenization with a tissuegrinder/Teflon pestle. Membranes were collected by centrifugation at30,000×g for 15 min at 4° C. and pellets were resuspended in hypotonicbuffer to a final concentration of 1-3 mg/mL. Protein concentrationswere determined using the BioRad protein assay reagent with bovine serumalbumen as standard. Aliquots of κ receptor membranes were stored at−80° C.

Radioligand dose displacement assays used 0.4 nM [³H]-U69,593 (GEHealthcare, Piscataway, N.J.; 40 Ci/mmole) with 15 μg membrane protein(recombinant κ opioid receptor expressed in HEK 293 cells; in-houseprep) in a final volume of 200 μl binding buffer (5% DMSO, 50 mM Trizmabase, pH 7.4). Non-specific binding was determined in the presence of 10μM unlabeled naloxone or U69,593. All reactions were performed in96-well polypropylene plates for 1 hour at a temperature of about 25° C.Binding reactions were terminated by rapid filtration onto 96-wellUnifilter GF/C filter plates (Perkin Elmer, Shelton, Conn.) presoaked in0.5% polyethylenimine (Sigma). Harvesting was performed using a 96-welltissue harvester (Perkin Elmer, Shelton, Conn.) followed by fivefiltration washes with 200 μl ice-cold binding buffer. Filter plateswere subsequently dried at 50° C. for 1-2 hours. Fifty μl/wellscintillation cocktail (Perkin Elmer, Shelton, Conn.) was added andplates were counted in a Packard Top-Count for 1 min/well.

κ-Opioid Receptor Binding Data:

In certain embodiments, Compounds of the Invention exhibit a K_(i) (nM)for κ receptors of about 10,000 or more (which, for purposes of thisinvention, is interpreted as having no binding to the κ receptors).Certain Compounds of the Invention exhibit a K_(i) (nM) of about 20,000or less, or about 10,000 or less, or about 5,000 or less, or about 1,000or less, or about 500 or less, or about 450 or less, or about 350 orless, or about 200 or less, or about 100 or less, or about 50 or less,or about 10 or less, or about 1 or less, or about 0.1 or less.

κ-Opioid Receptor

Functional Assay Procedures: Functional [³⁵S]GTPγS binding assays wereconducted as follows. K opioid receptor membrane solution was preparedby sequentially adding final concentrations of 0.026 μg/μl κ membraneprotein (in-house), 10 μg/mL saponin, 3 μM GDP and 0.20 nM [³⁵S]GTPγS tobinding buffer (100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice.The prepared membrane solution (190 μl/well) was transferred to96-shallow well polypropylene plates containing 10 μl of 20×concentrated stock solutions of agonist prepared in DMSO. Plates wereincubated for 30 min at a temperature of about 25° C. with shaking.Reactions were terminated by rapid filtration onto 96-well UnifilterGF/B filter plates (Perkin Elmer, Shelton, Conn.) using a 96-well tissueharvester (Packard) and followed by three filtration washes with 200 μlice-cold binding buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filterplates were subsequently dried at 50° C. for 2-3 hours. Fifty l/wellscintillation cocktail (Perkin Elmer, Shelton, Conn.) was added andplates were counted in a Packard Top-Count for 1 min/well.

κ-Opioid Receptor Functional Data:

κ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a κ receptor. Certain Compounds ofthe Invention exhibit a κ GTP EC₅₀ (nM) of about 20,000 or less tostimulate κ opioid receptor function, or about 10,000 or less, or about5,000 or less, or about 2,000 or less, or about 1,500 or less, or about1,000 or less, or about 600 or less, or about 100 or less, or about 50or less, or about 25 or less, or about 10 or less, or about 1 or less,or about 0.1 or less.

κ GTP E_(max) (%) is the maximal effect elicited by a compound relativeto the effect elicited by U69,593. Certain Compounds of the Inventionexhibit a κ GTP E_(max) (%) of greater than about 1%, or greater thanabout 5%, or greater than about 10%, or greater than about 20%, orgreater than about 50%, or greater than about 75%, or greater than about90%, or greater than about 100%.

δ-Opioid Receptor Binding Assay Procedures:

δ-Opioid Receptor Binding Assay Procedures can be conducted as follows.Radioligand dose-displacement assays use 0.3 nM [³H]-Naltrindole (PerkinElmer, Shelton, Conn.; 33.0 Ci/mmole) with 5 μg membrane protein (PerkinElmer, Shelton, Conn.) in a final volume of 500 μl binding buffer (5 mMMgCl₂, 5% DMSO, 50 mM Trizma base, pH 7.4). Non-specific binding isdetermined in the presence of 25 μM unlabeled naloxone. All reactionsare performed in 96-deep well polypropylene plates for 1 hour at atemperature of about 25° C. Binding reactions are terminated by rapidfiltration onto 96-well Unifilter GF/C filter plates (Perkin Elmer,Shelton, Conn.) presoaked in 0.5% polyethylenimine (Sigma). Harvestingis performed using a 96-well tissue harvester (Perkin Elmer, Shelton,Conn.) followed by five filtration washes with 500 μl ice-cold bindingbuffer. Filter plates are subsequently dried at 50° C. for 1-2 hours.Fifty μl/well scintillation cocktail (Perkin Elmer, Shelton, Conn.) areadded and plates are counted in a Packard Top-Count for 1 min/well.

δ-Opioid Receptor Binding Data:

In certain embodiments, Compounds of the Invention can exhibit a K_(i)(nM) for δ receptors of about 10,000 or more (which, for the purposes ofthis invention, is interpreted as having no binding to the δ receptors).Certain Compounds of the Invention can exhibit a K_(i) (nM) of about20,000 or less, or about 10,000 or less, or about 9,000 or less, orabout 7,500 or less, or about 6,500 or less, or about 5,000 or less, orabout 3,000 or less, or about 2,500 or less, or about 1,000 or less, orabout 500 or less, or about 350 or less, or about 250 or less, or about100 or less, or about 10 or less for δ receptors.

δ-Opioid Receptor Functional Assay Procedures:

Functional [³⁵S]GTPγS binding assays are conducted as follows. δ opioidreceptor membrane solution is prepared by sequentially adding finalconcentrations of 0.026 μg/μl δ membrane protein (Perkin Elmer, Shelton,Conn.), 10 μg/mL saponin, 3 μM GDP and 0.20 nM [³⁵S]GTPγS to bindingbuffer (100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice. Theprepared membrane solution (190 μl/well) is transferred to 96-shallowwell polypropylene plates containing 10 μl of 20× concentrated stocksolutions of agonist prepared in DMSO. Plates are incubated for 30 minat a temperature of about 25° C. with shaking. Reactions are terminatedby rapid filtration onto 96-well Unifilter GF/B filter plates (PerkinElmer, Shelton, Conn.) using a 96-well tissue harvester (Packard) andfollowed by three filtration washes with 200 μl ice-cold binding buffer(10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates are subsequentlydried at 50° C. for 1-2 hours. Fifty μl/well scintillation cocktail(Perkin Elmer, Shelton, Conn.) are added and plates are counted in aPackard Top-count for 1 min/well.

δ-Opioid Receptor Functional Data:

δ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a δ receptor. Certain Compounds ofthe Invention can exhibit a δ GTP EC₅₀ (nM) of about 20,000 or less, orabout 10,000 or less, or about 3,500 or less, or about 1,000 or less, orabout 500 or less, or about 100 or less, or about 90 or less, or about50 or less, or about 25 or less, or about 10 or less.

δ GTP E_(max) (%) is the maximal effect elicited by a compound relativeto the effect elicited by met-enkephalin. Certain Compounds of theInvention can exhibit a δ GTP E_(max) (%) of greater than about 1%, orgreater than about 5%, or greater than about 10%, or greater than about30%, or greater than about 50%, or greater than about 75%, or greaterthan about 90%, or greater than about 100%.

ORL-1 Receptor Binding Assay Procedure:

Membranes from recombinant HEK-293 cells expressing the human opioidreceptor-like receptor (ORL-1) (Perkin Elmer, Shelton, Conn.) can beprepared by lysing cells in ice-cold hypotonic buffer (2.5 mM MgCl₂, 50mM HEPES, pH 7.4) (10 ml/10 cm dish) followed by homogenization with atissue grinder/Teflon pestle. Membranes are collected by centrifugationat 30,000×g for 15 min at 4° C. and pellets resuspended in hypotonicbuffer to a final concentration of 1-3 mg/ml. Protein concentrations aredetermined using the BioRad protein assay reagent with bovine serumalbumen as standard. Aliquots of the ORL-1 receptor membranes are storedat −80° C.

Radioligand binding assays (screening and dose-displacement) use 0.1 nM[³H]-nociceptin (Perkin Elmer, Shelton, Conn.; 87.7 Ci/mmole) with 12 μgmembrane protein in a final volume of 500 μl binding buffer (10 mMMgCl₂, 1 mM EDTA, 5% DMSO, 50 mM HEPES, pH 7.4). Non-specific binding isdetermined in the presence of 10 nM unlabeled nociceptin (AmericanPeptide Company). All reactions are performed in 96-deep wellpolypropylene plates for 1 h at room temperature. Binding reactions areterminated by rapid filtration onto 96-well Unifilter GF/C filter plates(Perkin Elmer, Shelton, Conn.) presoaked in 0.5% polyethylenimine(Sigma). Harvesting is performed using a 96-well tissue harvester(Perkin Elmer, Shelton, Conn.) followed by three filtration washes with500 μl ice-cold binding buffer. Filter plates are subsequently dried at50° C. for 2-3 hours. Fifty μl/well scintillation cocktail (PerkinElmer, Shelton, Conn.) is added and plates are counted in a PackardTop-Count for 1 min/well. The data from screening and dose-displacementexperiments are analyzed using Microsoft Excel and the curve fittingfunctions in GraphPad PRISM™, v. 3.0 or higher, respectively, or anin-house function for one-site competition curve-fitting.

ORL-1 Receptor Binding Data:

Certain Compounds of the Invention can have a K_(i) (nM) of about 20,000or less, e.g., about 5,000 or less. In certain embodiments, Compounds ofthe Invention have a K_(i) (nM) of about 1,000 or less, or about 500 orless, or about 300 or less, or about 100 or less, or about 50 or less,or about 20 or less, or about 10 or less, or about 1 or less, or about0.1 or less.

ORL-1 Receptor Functional Assay Procedure:

Membranes from recombinant HEK-293 cells expressing the human opioidreceptor-like (ORL-1) (Perkin Elmer, Shelton, Conn.) can be prepared bylysing cells in ice-cold hypotonic buffer (2.5 mM Mg Cl₂, 50 mM HEPES,pH 7.4) (10 ml/10 cm dish) followed by homogenization with a tissuegrinder/Teflon pestle. Membranes are collected by centrifugation at30,000×g for 15 min at 4° C., and pellets resuspended in hypotonicbuffer to a final concentration of 1-3 mg/ml. Protein concentrations aredetermined using the BioRad protein assay reagent with bovine serumalbumen as standard. Aliquots of the ORL-1 receptor membranes are storedat −80° C.

Functional [³⁵S]GTPγS binding assays are conducted as follows. ORL-1membrane solution is prepared by sequentially adding finalconcentrations of 0.026 μg/μl ORL-1 membrane protein, 10 μg/ml saponin,3 μM GDP and 0.20 nM [³⁵S]GTPγS to binding buffer (100 mM NaCl, 10 mMMgCl₂, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190μl/well) is transferred to 96-shallow well polypropylene platescontaining 10 μl of 20× concentrated stock solutions ofagonist/nociceptin prepared in DMSO. Plates are incubated for 30 min atroom temperature with shaking. Reactions are terminated by rapidfiltration onto 96-well Unifilter GF/B filter plates (Perkin Elmer,Shelton, Conn.) using a 96-well tissue harvester (Packard) and followedby three filtration washes with 200 μl ice-cold binding buffer (10 mMNaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates are subsequently dried at50° C. for 2-3 hours. Fifty μl/well scintillation cocktail (PerkinElmer, Shelton, Conn.) is added and plates are counted in a PackardTop-Count for 1 min/well. Data are analyzed using the sigmoidaldose-response curve fitting functions in GraphPad PRISM v. 3.0 orhigher, or an in-house function for non-linear, sigmoidal dose-responsecurve-fitting.

ORL-1 Receptor Functional Data:

ORL-1 GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at an ORL-1 receptor. In certainembodiments, the Compounds of the Invention that have a high bindingaffinity (i.e. low K_(i) value) can have an ORL-1 GTP EC₅₀ (nM) ofgreater than about 10,000 (i.e. will not stimulate at therapeuticconcentrations) In certain embodiments, Compounds of the Invention havean ORL-1 GTP EC₅₀ (nM) of about 20,000 or less, or about 10,000 or less,or about 5000 or less, or about 1000 or less, or about 100 or less, orabout 10 or less, or about 1 or less, or about 0.1 or less.

ORL-1 GTP E_(max)% is the maximal effect elicited by a compound relativeto the effect elicited by nociceptin, a standard ORL-1 agonist. Incertain embodiments, Compounds of the Invention have an ORL-1 GTPE_(max) of less than 10% (which, for the purposes of this invention, isinterpreted as having antagonist activity at ORL-1 receptors). CertainCompounds of the Invention can have an ORL-1 GTP E_(max) (%) of greaterthan about 1%, or greater than about 5%, or greater than about 10%, orgreater than about 20%, or greater than about 50%, or greater than about75%, or greater than about 88%, or of greater than about 100%.

In Vivo Assays for Pain

Test Animals:

Each experiment uses rats weighing between 200-260 g at the start of theexperiment. The rats are group-housed and have free access to food andwater at all times, except prior to oral administration of a Compound ofthe Invention when food is removed for about 16 hours before dosing. Acontrol group acts as a comparison to rats treated with a Compound ofthe Invention. The control group is administered the carrier for theCompound of the Invention. The volume of carrier administered to thecontrol group is the same as the volume of carrier and Compound of theInvention administered to the test group.

Acute Pain:

To assess the actions of a Compound of the Invention for the treatmentor prevention of acute pain, the rat tail flick can be used. Rats aregently restrained by hand and the tail exposed to a focused beam ofradiant heat at a point 5 cm from the tip using a tail flick unit (Model7360, commercially available from Ugo Basile of Italy). Tail flicklatencies are defined as the interval between the onset of the thermalstimulus and the flick of the tail. Animals not responding within 20seconds are removed from the tail flick unit and assigned a withdrawallatency of 20 seconds. Tail flick latencies are measured immediatelybefore (pre-treatment) and 1, 3, and 5 hours following administration ofa Compound of the Invention. Data are expressed as tail flick latency(s)and the percentage of the maximal possible effect (% MPE), i.e., 20seconds, is calculated as follows:

${\% \mspace{14mu} {MPE}} = {\frac{\begin{bmatrix}{\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {latency}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {latency}} \right)\end{bmatrix}}{\left( {{20\mspace{14mu} s} - {{pre}\text{-}{administration}\mspace{14mu} {latency}}} \right)} \times 100}$

The rat tail flick test is described in F. E. D'Amour et al., “A Methodfor Determining Loss of Pain Sensation,” J Pharmacol. Exp. Ther.72:74-79 (1941).

To assess the actions of a Compound of the Invention for the treatmentor prevention of acute pain, the rat hot plate test can also be used.Rats are tested using a hot plate apparatus consisting of a clearplexiglass cylinder with a heated metal floor maintained at atemperature of 48-52° C. (Model 7280, commercially available from UgoBasile of Italy). A rat is placed into the cylinder on the hot plateapparatus for a maximum duration of 30 s, or until it exhibits anocifensive behavior (behavioral endpoint), at which time it is removedfrom the hot plate, and the response latency recorded. Hot platelatencies are measured immediately before (pre-treatment) and 1, 3, and5 hours following administration of a Compound of the Invention. Thenocifensive behavioral endpoint is defined as any of the following: 1)paw withdrawal, either as a sustained lift or with shaking or licking;2) alternating foot lifting; 3) escape or attempted escape from thetesting device; or 4) vocalization. Data are expressed as responselatency(s) and the percentage of the maximal possible effect iscalculated as described above for the tail flick test. The hot platetest is described in G. Woolfe and A. D. MacDonald, J. Pharmacol. Exp.Ther. 80:300-307 (1944).

Inflammatory Pain:

To assess the actions of a Compound of the Invention for the treatmentor prevention of inflammatory pain, the Freund's complete adjuvant(“FCA”) model of inflammatory pain can be used. FCA-induced inflammationof the rat hind paw is associated with the development of persistentinflammatory mechanical hyperalgesia and provides reliable prediction ofthe anti-hyperalgesic action of clinically useful analgesic drugs (L.Bartho et al., “Involvement of Capsaicin-sensitive Neurones inHyperalgesia and Enhanced Opioid Antinociception in Inflammation,”Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670 (1990)). Theleft hind paw of each animal is administered a 50 μL intraplantarinjection of 50% FCA. Prior to injection of FCA (baseline) and 24 hourpost injection, the animal is assessed for response to noxiousmechanical stimuli by determining the PWT, as described below. Rats arethen administered a single injection of 1, 3, or 10 mg/kg of either aCompound of the Invention; 30 mg/kg of a control drug selected fromCelebrex, indomethacin or naproxen; or carrier. Responses to noxiousmechanical stimuli are determined 1, 3, 5 and 24 hours postadministration. Percentage reversal of hyperalgesia for each animal isdefined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\begin{bmatrix}{\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)\end{bmatrix}}{\left\lbrack {\left( {{baseline}\mspace{14mu} {PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)} \right\rbrack} \times 100}$

Neuropathic Pain:

To assess the actions of a Compound of the Invention for the treatmentor prevention of neuropathic pain, either the Seltzer model or the Chungmodel can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats (Z.Seltzer et al., “A Novel Behavioral Model of Neuropathic Pain DisordersProduced in Rats by Partial Sciatic Nerve Injury,” Pain 43:205-218(1990)). Partial ligation of the left sciatic nerve is performed underisoflurane/O₂ inhalation anaesthesia. Following induction of anesthesia,the left thigh of the rat is shaved and the sciatic nerve exposed athigh thigh level through a small incision and is carefully cleared ofsurrounding connective tissues at a site near the trocanther just distalto the point at which the posterior biceps semitendinosus nerve branchesoff of the common sciatic nerve. A 7-0 silk suture is inserted into thenerve with a ⅜ curved, reversed-cutting mini-needle and tightly ligatedso that the dorsal ⅓ to ½ of the nerve thickness is held within theligature. The wound is closed with a single muscle suture (4-0 nylon(Vicryl)) and vetbond tissue glue. Following surgery, the wound area isdusted with antibiotic powder. Sham-treated rats undergo an identicalsurgical procedure except that the sciatic nerve is not manipulated.Following surgery, animals are weighed and placed on a warm pad untilthey recover from anesthesia. Animals are then returned to their homecages until behavioral testing begins. The animal is assessed forresponse to noxious mechanical stimuli by determining PWT, as describedbelow, prior to surgery (baseline), then immediately prior to and 1, 3,and 5 hours after drug administration.

${\% \mspace{14mu} {Reversal}} = {\frac{\begin{bmatrix}{\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)\end{bmatrix}}{\left\lbrack {\left( {{baseline}\mspace{14mu} {PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)} \right\rbrack} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anaesthesia. Following induction of anaesthesia, a 3 cmincision is made and the left paraspinal muscles are separated from thespinous process at the L₄-S₂ levels. The L₆ transverse process iscarefully removed with a pair of small rongeurs to identify visually theL₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) isisolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is notmanipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered a Compound of theInvention. The animal can also be assessed for response to noxiousthermal stimuli or for tactile allodynia, as described below. The Chungmodel for neuropathic pain is described in S. H. Kim, “An ExperimentalModel for Peripheral Neuropathy Produced by Segmental Spinal NerveLigation in the Rat,” Pain 50(3):355-363 (1992).

Response to Mechanical Stimuli as an Assessment of MechanicalHyperalgesia:

The paw pressure assay can be used to assess mechanical hyperalgesia.For this assay, hind paw withdrawal thresholds (PWT) to a noxiousmechanical stimulus are determined using an analgesymeter (Model 7200,commercially available from Ugo Basile of Italy) as described in C.Stein, “Unilateral Inflammation of the Hindpaw in Rats as a Model ofProlonged Noxious Stimulation: Alterations in Behavior and NociceptiveThresholds,” Pharmacol. Biochem. and Behavior 31:451-455 (1988). The ratis gently restrained, its hindpaw is placed on a small round platform,and punctate pressure is applied to the dorsal surface of the hindpaw ina graded manner. The maximum weight that is applied to the hind paw isset at 250 g and the end point is taken as complete withdrawal of thepaw. PWT is determined once for each rat at each time point and eitheronly the affected (ipsilateral; same side as the injury) rear paw istested, or both the ipsilateral and contralateral (non-injured; oppositeto the injury) rear paw are tested.

Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia:

The plantar test can be used to assess thermal hyperalgesia. For thistest, hind paw withdrawal latencies to a noxious thermal stimulusapplied to the plantar surface of the hindpaw are determined using aplantar test apparatus (commercially available from Ugo Basile of Italy)following the technique described by K. Hargreaves et al., “A New andSensitive Method for Measuring Thermal Nociception in CutaneousHyperalgesia,” Pain 32(1):77-88 (1988). The maximum exposure time is setat 32 seconds to avoid tissue damage and any directed paw withdrawalfrom the heat source is taken as the end point. Three latencies aredetermined at each time point and averaged. Either only the affected(ipsilateral) paw is tested, or both the ipsilateral and contralateral(non-injured) paw are tested.

Assessment of Tactile Allodynia:

To assess tactile allodynia, rats are placed in clear, plexiglasscompartments with a wire mesh floor and allowed to habituate for aperiod of at least 15 minutes. After habituation, a series of von Freymonofilaments are presented to the plantar surface of the affected(ipsilateral) foot of each rat. The series of von Frey monofilamentsconsists of six monofilaments of increasing diameter, with the smallestdiameter fiber presented first. Five trials are conducted with eachfilament with each trial separated by approximately 2 minutes. Eachpresentation lasts for a period of 4-8 seconds or until a nociceptivewithdrawal behavior is observed. Flinching, paw withdrawal or licking ofthe paw are considered nociceptive behavioral responses.

Assessment of Respiratory Depression:

To assess respiratory depression, rats can be prepared by implanting afemoral artery cannula via which blood samples are taken. Blood samplesare taken prior to drug administration, then 1, 3, 5 and 24 hourspost-treatment. Blood samples are processed using an arterial blood gasanalyzer (e.g., IDEXX VetStat with Respiratory/Blood Gas testcartridges). Comparable devices are a standard tool for blood gasanalysis (e.g., D. Torbati et al., Intensive Care Med (26): 585-591(2000).

Assessment of Gastric Motility.

Animals are treated with vehicle, reference compound or test article byoral gavage at a volume of 10 mL/kg. At one hour post-dose, all animalsare treated with charcoal meal solution (5% non-activated charcoalpowder in a solution of 1% carboxymethylcellulose in water) at a volumeof 10 mL/kg. At two hours post-dose (one hour post-charcoal), animalsare sacrificed by carbon dioxide inhalation or isoflurane overdose andthe transit of charcoal meal identified. The stomach and small intestineare removed carefully and each placed on a saline-soaked absorbentsurface. The distance between the pylorus and the furthest progressionof charcoal meal is measured and compared to the distance between thepylorus and the ileocecal junction. The charcoal meal transit isexpressed as a percentage of small intestinal length traveled.

Pharmaceutical Compositions

Due to their activity, the Compounds of the Invention are advantageouslyuseful in human and veterinary medicine. As described above, theCompounds of the Invention are useful for treating or preventing aCondition in a patient in need thereof. The Compounds of the Inventioncan be administered to any patient requiring modulation of the opioidreceptors. The term “patient” as used herein refers to any animal thatmay experience the beneficial effects of a Compound of the Invention.Foremost such animals are mammals, e.g., humans and companion animals,although the invention is not intended to be so limited.

When administered to a patient, a Compound of the Invention can beadministered as a component of a composition that comprises apharmaceutically acceptable carrier or excipient. A Compound of theInvention can be administered by any appropriate route, as determined bythe medical practitioner. Methods of administration may includeintradermal, intramuscular, intraperitoneal, parenteral, intravenous,subcutaneous, intranasal, epidural, oral, sublingual, buccal,intracerebral, intravaginal, transdermal, transmucosal, rectal, byinhalation, or topical (particularly to the ears, nose, eyes, or skin).Delivery can be either local or systemic. In certain embodiments,administration will result in the release of a Compound of the Inventioninto the bloodstream.

Pharmaceutical compositions of the invention can take the form ofsolutions, suspensions, emulsions, tablets, pills, pellets, powders,multi-particulates, capsules, capsules containing liquids, capsulescontaining powders, capsules containing multi-particulates, lozenges,sustained-release formulations, suppositories, transdermal patches,transmucosal films, sub-lingual tablets or tabs, aerosols, sprays, orany other form suitable for use. In one embodiment, the composition isin the form of a tablet. In another embodiment, the composition is inthe form of a capsule (see, e.g., U.S. Pat. No. 5,698,155). Otherexamples of suitable pharmaceutical excipients are described inRemington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed.,19th ed. 1995), incorporated herein by reference.

Pharmaceutical compositions of the invention preferably comprise asuitable amount of a pharmaceutically acceptable excipient so as toprovide the form for proper administration to the patient. Such apharmaceutical excipient can be a diluent, suspending agent,solubilizer, binder, disintegrant, preservative, coloring agent,lubricant, and the like. The pharmaceutical excipient can be a liquid,such as water or an oil, including those of petroleum, animal,vegetable, or synthetic origin, such as peanut oil, soybean oil, mineraloil, sesame oil, and the like. The pharmaceutical excipient can besaline, gum acacia, gelatin, starch paste, talc, keratin, colloidalsilica, urea, and the like. In addition, auxiliary, stabilizing,thickening, lubricating, and coloring agents can be used. In oneembodiment, the pharmaceutically acceptable excipient is sterile whenadministered to a patient. Water is a particularly useful excipient whena Compound of the Invention is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid excipients, particularly for injectable solutions.Suitable pharmaceutical excipients also include starch, glucose,lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodiumstearate, glycerol monostearate, talc, sodium chloride, dried skim milk,glycerol, propylene glycol, water, ethanol, and the like. The inventioncompositions, if desired, can also contain minor amounts of wetting oremulsifying agents, or pH buffering agents. Specific examples ofpharmaceutically acceptable carriers and excipients that can be used toformulate oral dosage forms are described in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (1986).

In certain embodiments, the Compounds of the Invention are formulatedfor oral administration. A Compound of the Invention to be orallydelivered can be in the form of tablets, capsules, gelcaps, caplets,lozenges, aqueous or oily solutions, suspensions, granules, powders,emulsions, syrups, or elixirs, for example. When a Compound of theInvention is incorporated into oral tablets, such tablets can becompressed, tablet triturates, enteric-coated, sugar-coated,film-coated, multiply compressed or multiply layered.

An orally administered Compound of the Invention can contain one or moreadditional agents such as, for example, sweetening agents such asfructose, aspartame or saccharin; flavoring agents such as peppermint,oil of wintergreen, or cherry; coloring agents; and preserving agents,and stabilizers, to provide stable, pharmaceutically palatable dosageforms. Techniques and compositions for making solid oral dosage formsare described in Pharmaceutical Dosage Forms: Tablets (Lieberman,Lachman and Schwartz, eds., 2nd ed.) published by Marcel Dekker, Inc.Techniques and compositions for making tablets (compressed and molded),capsules (hard and soft gelatin) and pills are also described inRemington's Pharmaceutical Sciences 1553-1593 (Arthur Osol, ed., 16^(th)ed., Mack Publishing, Easton, Pa. 1980). Liquid oral dosage formsinclude aqueous and nonaqueous solutions, emulsions, suspensions, andsolutions and/or suspensions reconstituted from non-effervescentgranules, optionally containing one or more suitable solvents,preservatives, emulsifying agents, suspending agents, diluents,sweeteners, coloring agents, flavoring agents, and the like. Techniquesand compositions for making liquid oral dosage forms are described inPharmaceutical Dosage Forms: Disperse Systems, (Lieberman, Rieger andBanker, eds.) published by Marcel Dekker, Inc.

When a Compound of the Invention is formulated for parenteraladministration by injection (e.g., continuous infusion or bolusinjection), the formulation can be in the form of a suspension,solution, or emulsion in an oily or aqueous vehicle, and suchformulations can further comprise pharmaceutically necessary additivessuch as one or more stabilizing agents, suspending agents, dispersingagents, and the like. When a Compound of the Invention is to be injectedparenterally, it can be, e.g., in the form of an isotonic sterilesolution. A Compound of the Invention can also be in the form of apowder for reconstitution as an injectable formulation.

In certain embodiments, a Compound of the Invention is formulated into apharmaceutical composition for intravenous administration. Typically,such compositions comprise sterile isotonic aqueous buffer. Wherenecessary, the compositions can also include a solubilizing agent. ACompound of the Invention for intravenous administration can optionallyinclude a local anesthetic such as benzocaine or prilocaine to lessenpain at the site of the injection. Generally, the ingredients aresupplied either separately or mixed together in unit dosage form, forexample, as a dry lyophilized powder or water free concentrate in ahermetically sealed container such as an ampule or sachette indicatingthe quantity of active agent. Where a Compound of the Invention is to beadministered by infusion, it can be dispensed, for example, with aninfusion bottle containing sterile pharmaceutical grade water or saline.Where a Compound of the Invention is administered by injection, anampule of sterile water for injection or saline can be provided so thatthe ingredients can be mixed prior to administration.

When a Compound of the Invention is to be administered by inhalation, itcan be formulated into a dry aerosol, or an aqueous or partially aqueoussolution.

In another embodiment, a Compound of the Invention can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1527-1533(1990); and Treat et al., Liposomes in the Therapy of Infectious Diseaseand Cancer 317-327 and 353-365 (1989)).

In certain embodiments, a Compound of the Invention is administeredlocally. This can be achieved, for example, by local infusion duringsurgery, topical application, e.g., in conjunction with a wound dressingafter surgery, by injection, by means of a catheter, by means of asuppository or enema, or by means of an implant, said implant being of aporous, non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers.

In certain embodiments, a Compound of the Invention can be delivered inan immediate release form. In other embodiments, a Compound of theInvention can be delivered in a controlled-release system orsustained-release system. Controlled- or sustained-releasepharmaceutical compositions can have a common goal of improving drugtherapy over the results achieved by their non-controlled ornon-sustained-release counterparts. In one embodiment, a controlled- orsustained-release composition comprises a minimal amount of a Compoundof the Invention to treat or prevent the Condition (or a symptomthereof) in a minimum amount of time. Advantages of controlled- orsustained-release compositions include extended activity of the drug,reduced dosage frequency, and increased compliance. In addition,controlled- or sustained-release compositions can favorably affect thetime of onset of action or other characteristics, such as blood levelsof the Compound of the Invention, and can thus reduce the occurrence ofadverse side effects.

Controlled- or sustained-release compositions can initially immediatelyrelease an amount of a Compound of the Invention that promptly producesthe desired therapeutic or prophylactic effect, and gradually andcontinually release other amounts of the Compound of the Invention tomaintain a level of therapeutic or prophylactic effect over an extendedperiod of time. To maintain a constant level of the Compound of theInvention in the body, the Compound of the Invention can be releasedfrom the dosage form at a rate that will replace the amount of Compoundof the Invention being metabolized and excreted from the body.Controlled- or sustained-release of an active ingredient can bestimulated by various conditions, including but not limited to, changesin pH, changes in temperature, concentration or availability of enzymes,concentration or availability of water, or other physiologicalconditions or compounds.

Controlled-release and sustained-release means for use according to thepresent invention may be selected from those known in the art. Examplesinclude, but are not limited to, those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533;5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and5,733,566, each of which is incorporated herein by reference. Suchdosage forms can be used to provide controlled- or sustained-release ofone or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmoticsystems, multilayer coatings, microparticles, multiparticulates,liposomes, microspheres, or a combination thereof to provide the desiredrelease profile in varying proportions. Suitable controlled- orsustained-release formulations known in the art, including thosedescribed herein, can be readily selected for use with the activeingredients of the invention in view of this disclosure. See alsoGoodson, “Dental Applications” (pp. 115-138) in Medical Applications ofControlled Release, Vol. 2, Applications and Evaluation, R. S. Langerand D. L. Wise eds., CRC Press (1984). Other controlled- orsustained-release systems that are discussed in the review by Langer,Science 249:1527-1533 (1990) can be selected for use according to thepresent invention. In one embodiment, a pump can be used (Langer,Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref Biomed Eng. 14:201(1987); Buchwald et al., Surgery 88:507 (1980); and Saudek et al., N,Engl. J. Med 321:574 (1989)). In another embodiment, polymeric materialscan be used (see Medical Applications of Controlled Release (Langer andWise eds., 1974); Controlled Drug Bioavailability, Drug Product Designand Performance (Smolen and Ball eds., 1984); Ranger and Peppas, JMacromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy et al., Science228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); and Howard etal., J. Neurosurg. 71:105 (1989)). In yet another embodiment, acontrolled- or sustained-release system can be placed in proximity of atarget of a Compound of the Invention, e.g., the spinal column, brain,or gastrointestinal tract, thus requiring only a fraction of thesystemic dose.

When in tablet or pill form, a pharmaceutical composition of theinvention can be coated to delay disintegration and absorption in thegastrointestinal tract, thereby providing a sustained action over anextended period of time. Selectively permeable membranes surrounding anosmotically active driving compound are also suitable for orallyadministered compositions. In these latter platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time-delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions can includestandard excipients such as mannitol, lactose, starch, magnesiumstearate, sodium saccharin, cellulose, and magnesium carbonate. In oneembodiment, the excipients are of pharmaceutical grade.

Pharmaceutical compositions of the invention include single unit dosageforms suitable for oral administration such as, but not limited to,tablets, capsules, gelcaps, and caplets that are adapted for controlled-or sustained-release.

The amount of the Compound of the Invention that is effective for thetreatment or prevention of a condition can be determined by standardclinical techniques. In addition, in vitro and/or in vivo assays canoptionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed will also depend on, e.g., the route ofadministration and the extent of the Condition to be treated, and can bedecided according to the judgment of a practitioner and/or eachpatient's circumstances. Variations in dosing may occur depending upontypical factors such as the weight, age, gender and physical condition(e.g., hepatic and renal function) of the patient being treated, theaffliction to be treated, the severity of the symptoms, the frequency ofthe dosage interval, the presence of any deleterious side-effects, andthe particular compound utilized, among other things.

Suitable effective dosage amounts can range from about 0.01 mg/kg ofbody weight to about 3000 mg/kg of body weight of the patient per day,although they are typically from about 0.01 mg/kg of body weight toabout 2500 mg/kg of body weight of the patient per day or from about0.01 mg/kg of body weight to about 1000 mg/kg of body weight of thepatient per day. In one embodiment, the effective dosage amount is about100 mg/kg of body weight of the patient per day or less. In anotherembodiment, the effective dosage amount ranges from about 0.01 mg/kg ofbody weight to about 100 mg/kg of body weight of the patient per day ofa Compound of the Invention, in another embodiment, about 0.02 mg/kg ofbody weight to about 50 mg/kg of body weight of the patient per day, andin another embodiment, about 0.025 mg/kg of body weight to about 20mg/kg of body weight of the patient per day.

Administration can be as a single dose or as a divided dose. In oneembodiment, an effective dosage amount is administered about every 24hours until the Condition is abated. In another embodiment, an effectivedosage amount is administered about every 12 hours until the Conditionis abated. In another embodiment, an effective dosage amount isadministered about every 8 hours until the Condition is abated. Inanother embodiment, an effective dosage amount is administered aboutevery 6 hours until the Condition is abated. In another embodiment, aneffective dosage amount is administered about every 4 hours until theCondition is abated. The effective dosage amounts described herein referto total amounts administered; that is, if more than one Compound of theInvention is administered, the effective dosage amounts correspond tothe total amount administered.

Where a cell capable of expressing the μ-opioid receptors is contactedwith a Compound of the Invention in vitro, the amount effective forinhibiting or activating the μ-opioid receptors function in a cell cantypically range from about 10⁻¹² mol/L to about 10⁻⁴ mol/L, or fromabout 10⁻¹² mol/L to about 10⁻⁵ mol/L, or from about 10⁻¹² mol/L toabout 10⁻⁶ mol/L, or from about 10⁻¹² mol/L to about 10⁻⁹ mol/L of asolution or suspension of the Compound of the Invention in apharmaceutically acceptable carrier or excipient. In one embodiment, thevolume of solution or suspension comprising the Compound of theInvention can be from about 0.01 μL to about 1 mL. In anotherembodiment, the volume of solution or suspension can be about 200 μL.

Where a cell capable of expressing the δ-opioid receptors is contactedwith a Compound of the Invention in vitro, the amount effective forinhibiting or activating the δ-opioid receptors function in a cell cantypically range from about 10⁻¹² mol/L to about 10⁻⁴ mol/L, or fromabout 10⁻¹² mol/L to about 10⁻⁵ mol/L, or from about 10⁻¹² mol/L toabout 10⁻⁶ mol/L, or from about 10⁻¹² mol/L to about 10⁻⁹ mol/L of asolution or suspension of the Compound of the Invention in apharmaceutically acceptable carrier or excipient. In one embodiment, thevolume of solution or suspension comprising the Compound of theInvention can be from about 0.01 μL to about 1 mL. In anotherembodiment, the volume of solution or suspension can be about 200 μL.

Where a cell capable of expressing the κ-opioid receptors is contactedwith a Compound of the Invention in vitro, the amount effective forinhibiting or activating the κ-opioid receptors function in a cell cantypically range from about 10⁻¹² mol/L to about 10⁻⁴ mol/L, or fromabout 10⁻¹² mol/L to about 10⁻⁵ mol/L, or from about 10⁻¹² mol/L toabout 10⁻⁶ mol/L, or from about 10⁻¹² mol/L to about 10⁻⁹ mol/L of asolution or suspension of the Compound of the Invention in apharmaceutically acceptable carrier or excipient. In one embodiment, thevolume of solution or suspension comprising the Compound of theInvention can be from about 0.01 μL to about 1 mL. In anotherembodiment, the volume of solution or suspension can be about 200 μL.

Where a cell capable of expressing the ORL-1 receptor is contacted witha Compound of the Invention in vitro, the amount effective forinhibiting or activating the ORL-1 receptor function in a cell cantypically range from about 10⁻¹² mol/L to about 10⁻⁴ mol/L, or fromabout 10⁻¹² mol/L to about 10⁻⁵ mol/L, or from about 10⁻¹² mol/L toabout 10⁻⁶ mol/L, or from about 10⁻¹² mol/L to about 10⁻⁹ mol/L of asolution or suspension of the compound in a pharmaceutically acceptablecarrier or excipient. In one embodiment, the volume of solution orsuspension comprising the Compound of the Invention can be from about0.01 μL to about 1 mL. In another embodiment, the volume of solution orsuspension can be about 200 μL.

Compounds of the Invention can be assayed in vitro or in vivo for thedesired therapeutic or prophylactic activity prior to use in humans.Animal model systems can be used to demonstrate safety and efficacy.Certain Compounds of the Invention are expected to have an ED₅₀ fortreating inflammatory pain ranging from about 0.5 mg/kg to about 20mg/kg. Certain Compounds of the Invention are expected to producesignificant analgesia and/or anti-hyperalgesia at doses that do notinduce respiratory depression. In contrast, oxygen tension, oxygensaturation and pH are significantly decreased, while carbon dioxide issignificantly increased, in blood samples from rats given effectivedoses of conventional opioids, such as morphine.

According to the present invention, methods for treating or preventing aCondition in a patient in need thereof can further compriseco-administering to the patient an effective amount of a secondtherapeutic agent in addition to a Compound of the Invention (i.e., afirst therapeutic agent). An effective amount of the second therapeuticagent can be known or determinable by a medical practitioner in view ofthis disclosure and published clinical studies. In one embodiment of theinvention, where a second therapeutic agent is administered to a patientfor treatment of a Condition (e.g., pain), the minimal effective amountof the Compound of the Invention (i.e., the first therapeutic agent)will be less than its minimal effective amount would be in circumstanceswhere the second therapeutic agent is not administered. In thisembodiment, the Compound of the Invention and the second therapeuticagent can act either additively or synergistically to treat or prevent aCondition. Alternatively, the second therapeutic agent may be used totreat or prevent a disorder that is different from the Condition forwhich the first therapeutic agent is being administered, and whichdisorder may or may not be a Condition as defined hereinabove. In oneembodiment, a Compound of the Invention is administered concurrentlywith a second therapeutic agent as a single composition comprising aneffective amount of a Compound of the Invention and an effective amountof the second therapeutic agent. Alternatively, a composition comprisingan effective amount of a Compound of the Invention and a secondcomposition comprising an effective amount of the second therapeuticagent are concurrently administered. In another embodiment, an effectiveamount of a Compound of the Invention is administered prior orsubsequent to administration of an effective amount of the secondtherapeutic agent. In this embodiment, the Compound of the Invention isadministered while the second therapeutic agent exerts its therapeuticeffect, or the second therapeutic agent is administered while theCompound of the Invention exerts its therapeutic effect for treating orpreventing a Condition.

The second therapeutic agent can be, but is not limited to, an opioidagonist, a non-opioid analgesic, a non-steroidal anti-inflammatoryagent, an antimigraine agent, a Cox-IA inhibitor, a 5-lipoxygenaseinhibitor, an anti-emetic, a β-adrenergic blocker, an anticonvulsant, anantidepressant, a Ca²⁺-channel blocker, an anti-cancer agent, an agentfor treating or preventing UI, an agent for treating or preventinganxiety, an agent for treating or preventing a memory disorder, an agentfor treating or preventing obesity, an agent for treating or preventingconstipation, an agent for treating or preventing cough, an agent fortreating or preventing diarrhea, an agent for treating or preventinghigh blood pressure, an agent for treating or preventing epilepsy, anagent for treating or preventing anorexia/cachexia, an agent fortreating or preventing drug abuse, an agent for treating or preventingan ulcer, an agent for treating or preventing IBD, an agent for treatingor preventing IBS, an agent for treating or preventing addictivedisorder, an agent for treating or preventing Parkinson's disease andparkinsonism, an agent for treating or preventing a stroke, an agent fortreating or preventing a seizure, an agent for treating or preventing apruritic condition, an agent for treating or preventing psychosis, anagent for treating or preventing Huntington's chorea, an agent fortreating or preventing ALS, an agent for treating or preventing acognitive disorder, an agent for treating or preventing a migraine, anagent for treating, preventing or inhibiting vomiting, an agent fortreating or preventing dyskinesia, an agent for treating or preventingdepression, or any mixture thereof.

A composition of the invention is prepared by a method comprisingadmixing a Compound of the Invention with a pharmaceutically acceptablecarrier or excipient. Admixing can be accomplished using methods knownfor admixing a compound (or derivative) and a pharmaceuticallyacceptable carrier or excipient. In one embodiment, the Compound of theInvention is present in the composition in an effective amount.

The present invention also relates to a kit, comprising a sterilecontainer containing an effective amount of a Compound of the Inventionand instructions for therapeutic use.

The following examples are illustrative, but not limiting, of thecompounds, compositions and methods of the present invention. Suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art in view of this disclosure arewithin the spirit and scope of the invention.

EXAMPLES Example 1 Synthesis of ethyl2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetate(Compound 1)

Step A:(4R,4aS,7aR,12bS)-3-allyl-4a-hydroxy-9-methoxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(Compound 2)

To a solution of naloxone (50 g, 125 mmol) in 50 mL of DMF was addedK₂CO₃ (51.8 g, 375 mmol). The resulting suspension was stirred atambient temperature for 30 min whereupon methyl iodide (7.82 mL, 125mmol) in 7 mL of DMF was added dropwise via an addition funnel. Thesuspension was maintained overnight at ambient temperature. The reactionmixture was added to 1 L of H₂O and a white precipitate formed. Themixture was stirred for 1 h then filtered to give a white solid. Thesolid was dissolved in CH₂Cl₂ (700 mL) and washed with 1 N NaOH (400mL). The layers were separated and the organic layer was concentrated togive a wet solid. Water was added and the solid was subsequentlyfiltered and dried overnight in a vacuum oven to afford 28.1 g (66%) ofCompound 2 as a white solid. LC/MS, m/z=342.2 [M+H]⁺ (Calc: 342.40).

Step B:(4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(Compound 3)

Allylamine (36 g, 105 mmol) and 1,3-dimethylbarbituric acid (49.4 g, 316mmol) were added to a flask containing Compound 2 from Step A thendissolved in 180 mL CH₂Cl₂. Nitrogen was bubbled into the mixture for 10min. Pd(PPh₃)₄ (3.66 g, 3.16 mmol) was added and the yellow reactionmixture was heated at 40° C. under N₂ for 2 h. LC-MS revealed that thereaction was complete. The reaction mixture was transferred to aseparatory funnel and extracted with 1 N HCl (3×200 mL). The combinedaqueous layers were back extracted with CH₂Cl₂ (2×200 mL). The aqueouslayer was basified to pH=10 with 2.5 N NaOH. The basified aqueous wasextracted with CH₂Cl₂/MeOH (9:1) (3×300 mL). The combined organics weredried over MgSO₄, filtered, and concentrated to afford 12 g of a whitesolid. The pH of the aqueous layer was checked and found to be neutral.The aqueous layer was then basified to pH 10 with 2.5 N NaOH. Thebasified aqueous layer was again extracted with CH₂Cl₂/MeOH (9:1) (3×300mL). The combined organics were dried over MgSO₄, filtered, andconcentrated to afford 17 g of Compound 3 as a white solid. LC/MS,m/z=302.2 [M+H]⁺ (Calc: 302.34).

Step C:(4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-9-methoxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one(compound 4)

To a suspension of Compound 3 (9.5 g, 31.5 mmol) in 80 mL of CH₃CN wasadded K₂CO₃ (10.9 g, 79.0 mmol) portionwise followed bycyclopropylmethyl bromide (3.97 mL, 41.0 mmol) dropwise via syringe. Thesuspension was heated at reflux for 18 h. LC-MS showed a single peakcorresponding to the desired product (Tr=0.830 min, M+H=356). Themixture was cooled to ambient temperature and the solid was filtered offand washed with CH₃CN. The filtrate was concentrated and the goldenyellow residue was diluted with CH₂Cl₂ and H₂O. The layers wereseparated and the aqueous was further extracted with CH₂Cl₂. Thecombined organics were washed with brine, dried over MgSO₄, filtered,and concentrated to provide 9.76 g (87%) of Compound 4 as a white foamthat turned to a light yellow oily foam overnight. LC/MS, m/z=356.2[M+H]⁺ (Calc: 356.43).

Step D:(4bR,8aS,9R)-11-(cyclopropylmethyl)-4,8a-dihydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(Compound 5)

To a solution of Compound 4 (9.7 g, 12.7 mmol) in 100 mL of acetone wasadded saturated aqueous ammonium chloride solution (27 mL, 191 mmol) andzinc powder (7.14 g, 109 mmol). The resulting mixture was maintained at60° C. for 4.5 h. LC-MS analysis showed the reaction was complete. Thereaction mixture was cooled to ambient temperature and then filteredthrough Celite. The filter cake was rinsed with acetone and the filtratewas concentrated. The crude product was diluted with 300 mL CH₂Cl₂ and150 mL concentrated NH₄OH solution. The layers were separated and theaqueous layer was further extracted with CH₂Cl₂. The combined organicswere washed with brine, dried over Na₂SO₄, filtered and concentrated.Purification by flash chromatography on SiO₂ (ISCO ReadySep Rf 220 g0-50% acetone/hexanes) afforded 6.9 g (71%) of Compound 5 as a whitefoam. LC/MS, m/z=358.2 [M+H]⁺ (Calc: 358.44).

Step E:(4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-4-yltrifluoromethane sulfonate (Compound 6)

To a solution of Compound 5 (20.0 g, 56.0 mmol) in 370 mL of THF wasadded Cs₂CO₃ (23.7 g, 72.7 mmol) followed by PhNTf₂ (24.0 g, 67.1 mmol).The resulting yellow-orange mixture was maintained overnight at 70° C.LC-MS analysis showed the reaction was complete. The mixture wasconcentrated and diluted with CH₂Cl₂ and H₂O. The layers were separated.The aqueous layer was further extracted with CH₂Cl₂. The combinedorganics were washed with brine, dried over Na₂SO₄, filtered, andconcentrated to give 24.9 g (91%) of Compound 6 as an off-white/beigesolid. LC/MS, m/z=490.2 [M+H]⁺ (Calc: 490.51).

Step F:(4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H,4b-(epiminoethano)phenanthren-6(7H)-one(Compound 7)

To a solution of Compound 6 (15.0 g, 30.6 mmol) in 306 mL of THF wasadded Pd(OAc)₂ (0.688 g, 3.06 mmol) and dppp (1.26 g, 3.06 mmol). Et₃SiH(12.2 mL, 77.0 mmol) was dissolved in THF (30 mL) and added slowlydropwise via dropping funnel. The orange solution was maintainedovernight at ambient temperature. The resultant dark red/brown reactionmixture was then diluted with 300 mL Et₂O and extract three times with150 mL 1N HCl. The combined aqueous layers were washed with CH₂Cl₂(2×150 mL). LC-MS showed the product was in the acidic aqueous layer(pH=1). The aqueous was basified with concentrated NH₄OH. The white,milky aqueous layer was extracted with CH₂Cl₂ (3×200 mL). The combinedorganics were washed with brine, dried over Na₂SO₄, filtered andconcentrated. Purification by flash chromatography (ISCO ReadySep Rf,220 g, 0-40% acetone/hexanes) afforded 7.4 g (71%) of Compound 7 as awhite solid. LC/MS, m/z=342.2 [M+H]⁺ (Calc: 342.44).

Step G: Ethyl2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetate (Compound 1)

To a −78° C. solution of sodium hexamethyldisilazide (17.6 mL, 17.6mmol) in 34 mL of anhydrous THF was added a solution of Compound 7 (1.5g, 4.39 mmol) in 10 mL of THF dropwise via syringe. The pale yellowsolution was maintained at −10° C. for 20 min. The solution was cooledto −78° C. whereupon ethyl iodoacetate (2.1 mL, 17.6 mmol-passed throughbasic alumnina) was added dropwise (neat). The resulting yellow reactionmixture was allowed to slowly warm to ambient temperature overnight.

LC-MS analysis showed the reaction was complete. The reaction wasquenched with saturated aqueous NaHCO₃ and diluted with EtOAc. Thelayers were separated and the aqueous layer was further extracted withEtOAc (3×). The combined organics were washed with brine, dried overNa₂SO₄, filtered, and concentrated. Purification by flash chromatography(ISCO ReadySep Rf 80 g 0-50% EtOAc/hexanes) afforded 0.800 g (43%) ofCompound 1 as a light yellow oil. Compound 1 was further purified bymass-directed reverse phase preparative HPLC (20-90% AcCN/H₂O, 0.1% TFA)to provide 15 mg of a light yellow solid (after neutralization withammonium carbonate resin and lyophilization). ¹H NMR: δ_(H) (400 MHz,CD₃OD): 7.04 (d, 1H), 6.79 (s, 1H), 6.72 (d, 1H), 4.10-3.95 (m, 2H),3.74 (s, 3H), 3.41-3.31 (m, 1H), 3.20-3.00 (m, 2H), 2.90-2.55 (m, 3H),2.55-2.30 (m, 3H), 2.30-2.05 (m, 2H), 2.00 (dd, 1H), 1.95-1.85 (m, 1H),1.68 (app t, 1H), 1.17 (t, 3H), 1.00-0.85 (m, 1H), 0.65-0.45 (m, 2H),0.25-0.10 (m, 2H). LC/MS, m/z=428.1 [M+H]⁺ (Calc: 428.53).

Example 2 Synthesis of2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)aceticacid (Compound 8)

To a solution of Compound 1 (0.127 g, 0.297 mmol) from EXAMPLE 1 in 3.7mL of MeOH was added 1.78 mL of 2.5 N NaOH dropwise via syringe. Theresulting yellow solution was maintained for 18 h at ambienttemperature. LC-MS analysis showed that the reaction was complete. Thevolatiles were concentrated and the crude residue was purified byreverse phase mass-directed preparative HPLC (0-60% AcCN/H₂O, 0.1% TFA).The fractions were combined and lyophilized to afford 81 mg (68%) ofCompound 8 as a white, fluffy solid (TFA salt). ¹H NMR: δ_(H) (400 MHz,CD₃OD): 7.06 (d, 1H), 6.79 (brs, 1H), 6.75 (dd, 1H), 3.93 (d, 1H), 3.68(s, 3H), 3.31 3.22 (3H), 3.10 (d, 1H), 3.00-2.82 (m, 3H), 2.62-2.45 (m,2H), 2.42 (dd, 1H), 2.03 (dd, 1H), 1.88 (dd, 1H), 1.64 (app t, 1H), 1.33(d, 1H), 1.10-0.95 (m, 1H), 0.80-0.60 (m, 2H), 0.50-0.35 (m, 2H). LC/MS,m/z=400.2 [M+H]⁺ (Calc: 400.48).

Example 3 Synthesis of2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)aceticacid (Compound 9)

To a −10° C. solution of Compound 8 (0.055 g, 0.138 mmol) from EXAMPLE 2in CH₂Cl₂ was added a 1.0 M solution of BBr₃ in CH₂Cl₂ (0.690 mL, 0.688mmol) dropwise via syringe. The resulting yellow suspension wasmaintained at −10° C. for 2 h. LC-MS showed that the reaction was mostlycomplete. The reaction was quenched with 5 mL of MeOH and left overnightat ambient temperature. LC-MS analysis of the mixture after being leftat ambient temperature overnight now showed the formation of the methylester. The solution was concentrated and then redissolved in 3 mL MeOHand treated with 1 mL of 2.5 N NaOH and stirred for 3 h. Purification ofthe crude reaction mixture by mass-directed reverse-phase prep HPLC(0-40% AcCN/H₂O, 0.1% TFA) and subsequent lyophilization afforded 13 mg(25%) of Compound 9 as a fluffy, white solid (TFA salt). ¹H NMR: δ_(H)(400 MHz, CD₃OD): 7.05 (d, 1H), 6.78 (d, 1H), 6.68 (dd, 1H), 3.99 (d,1H), 3.40-3.20 (m, 4H), 3.16 (d, 1H) 3.10-3.00 (m, 1H), 3.00-2.85 (m,2H), 2.11 (dd, 1H), 1.99 (dd, 1H), 1.76 (app t, 1H), 1.38 (d, 1H),1.18-1.03 (m, 2H), 0.90-0.70 (m, 2H), 0.55-0.42 (m, 2H). LC/MS,m/z=386.3 [M+H]⁺ (Calc: 386.45).

Example 4 Synthesis of2,2′-((4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-7,7-diyl)diaceticacid (Compound 10)

Step A: Diethyl2,2′-((4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-7,7-diyl)diacetate(Compound 11)

To a −78° C. solution of NaHMDS (40 mL, 40 mmol) in 70 mL of anhydrousTHF was added a solution of Compound 7 (3.0 g, 8.79 mmol) from EXAMPLE 1in 30 mL of THF dropwise via syringe. The pale yellow solution wasmaintained at −10° C. for 15 min. The solution was cooled to −78° C.whereupon ethyl iodoacetate (4.67 mL, 40 mmol—passed through basicalumnina) was added dropwise (neat). The resulting yellow reactionmixture was allowed to slowly warm to ambient temperature overnight. Thereaction was quenched with saturated aqueous NaHCO₃ and diluted withEtOAc. The layers were separated and the aqueous layer was furtherextracted with EtOAc (3×). The combined organics were washed with brine,dried over Na₂SO₄, filtered, and concentrated. Purification by flashchromatography (ISCO ReadySep Rf 80 g 0-50% EtOAc/hexanes) afforded0.290 g of Compound 11 as a light yellow oil. LC/MS, m/z=514.3 [M+H]⁺(Calc: 514.45).

Step B:2,2′-((4bR,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-7,7-diyl)diaceticacid (Compound 10)

To a solution of Compound 11 (0.250 g, 0.487 mmol) from Step A in 8 mLof MeOH was added 1.0 mL of 2.5 N NaOH dropwise via syringe. Thereaction was maintained at ambient temperature for 7 h. LC-MS analysisshowed that the reaction was complete. Purification of the crudereaction mixture by reverse-phase preparative HPLC (0-60% AcCN/H₂O, 0.1%TFA) and subsequent lyophilization afforded 116 mg (52%) of Compound 10as a fluffy, white solid (TFA salt). ¹H NMR: δ_(H) (400 MHz, D2O): 7.15(d, 1H), 6.94 (d, 1H), 6.89 (dd, 1H), 3.35-3.22 (m, 3H), 3.20-3.08 (m,2H), 3.08-2.90 (m, 3H), 2.75-2.55 (m, 2H), 2.50 (ddd, 1H), 2.41 (d, 1H),2.15 (d, 1H), 1.48 (dd, 1H), 1.1-1.0 (m, 1H), 0.85-0.65 (m, 2H),0.48-0.35 (m, 2H). LC/MS, m/z=458.4 [M+H]⁺ (Calc: 458.52).

Example 5 Synthesis of2,2′-((4bR,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-7,7-diyl)diaceticacid (Compound 12)

To a −10° C. solution of Compound 10 (0.050 g, 0.109 mmol) from EXAMPLE4 in 2.78 mL of anhydrous CH₂Cl₂ was added a 1.0 M solution of BBr₃ inCH₂Cl₂ (0.550 mL, 0.550 mmol) dropwise via syringe. The resulting yellowsuspension was maintained at −10° C. for 2 h. LC-MS showed that thereaction was mostly complete The reaction was quenched with 5 mL of H₂Oand concentrated. The crude residue was dissolved in 1.3 mL of MeOH andtreated with 0.13 mL of 2.5 N NaOH dropwise via syringe. The reactionwas maintained overnight at ambient temperature. LC-MS showed that thereaction was complete. Purification of the reaction mixture bymass-directed reverse-phase prep HPLC (0-40% AcCN/H₂O, 0.1% TFA) andsubsequent lyophilization afforded 9 mg (32%) of Compound 12 as afluffy, white solid (TFA salt). ¹H NMR: δ_(H) (400 MHz, D₂O: 7.05 (d,1H), 6.81 (d, 1H), 6.74 (dd, 1H), 4.01 (brs, 1H), 3.30-3.18 (m, 3H),3.12-3.01 (m, 2H), 3.00-2.85 (m, 3H), 2.70-2.52 (m, 2H), 2.50-2.33 (m,2H), 2.15-2.05 (m, 2H), 1.42 (dd, 1H), 1.10-0.95 (m, 1H), 0.80-0.60 (m,2H), 0.45-0.30 (m, 2H). LC/MS, m/z=444.1 [M+H]⁺ (Calc: 444.49).

Example 6 Synthesis of(S)-2-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamido)propanoicacid (Compound 13)

Step A: (S)-methyl2-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamido)propanoate(Compound 14)

To a suspension of Compound 8 (0.150 g, 0.375 mmol) from EXAMPLE 2 in 3mL of DMF was added (S)-methyl 2-aminopropanoate hydrochloride (0.079 g,0.563 mmol) HATU (0.286 g, 0.751 mmol), and diisopropylethylamine (0.200mL, 1.13 mmol). The resulting yellow suspension was maintained overnightat ambient temperature. LC-MS analysis showed the reaction was complete.The crude reaction was concentrated on a Genevac at 50° C. for 18 h. Theresidue was diluted with CH₂Cl₂/MeOH, filtered, and concentrated.Purification by flash chromatography (ISCO ReadySep Rf, 40 g, 0-25%MeOH/CH₂Cl₂) afforded 0.166 g (91%) of Compound 14. LC/MS, m/z=485.4[M+H]⁺ (Calc: 485.58).

Step B:(S)-2-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamido)propanoic acid (Compound 13)

To a solution of Compound 14 (0.166 g, 0.343 mmol) in 3.5 mL of MeOH wasadded 0.69 mL of 2.5 N NaOH dropwise via syringe. The reaction wasmaintained at ambient temperature for 24 h. LC-MS analysis showed thatthe reaction was complete. Purification by reverse-phase preparativeHPLC (0-60% AcCN/H₂O, 0.1% TFA) and subsequent lyophilization afforded46 mg (28%) of Compound 13 as a fluffy, white solid (TFA salt). 1H NMR:δ_(H) (400 MHz, CD₃OD): 7.15 (d, 1H), 6.89 (d, 1H), 6.83 (dd, 1H), 4.32(q, 1H), 4.01 (d, 1H), 3.76 (s, 3H), 3.40-3.22 (m, 4H), 3.20 (d, 1H),3.06 (dd, 1H), 3.02-2.90 (m, 2H), 2.72-2.50 (m, 3H), 2.13 (dd, 1H), 1.87(dd, 1H), 1.69 (app t, 1H), 1.42 (d, 1H), 1.35 (d, 3H), 1.18-1.05 (m,1H), 0.90-0.80 (m, 1H), 0.80-0.70 (m, 1H), 0.58-0.45 (m, 2H). LC/MS,m/z=471.3 [M+H]⁺ (Calc: 471.56).

Example 7 Synthesis of(S)-2-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epimnoethano)phenanthren-7-yl)acetamido)propanoicacid (Compound 15)

To a 0° C. solution of Compound 13 (0.030 g, 0.064 mmol) from EXAMPLE 6in 2 mL of anhydrous CH₂Cl₂ was added a 1.0 M solution of BBr₃ in CH₂Cl₂(0.320 mL, 0.320 mmol) dropwise via syringe. The resulting yellowsuspension was maintained at 0° C. for 3 h. LC-MS showed that thereaction was mostly complete. The reaction was quenched with 5 mL ofMeOH and stirred at ambient temperature for 1 h. LC-MS showed a mixtureof phenol acid and the corresponding methyl ester. The solution wasconcentrated.

The crude residue was redissolved in 3 mL of MeOH and treated with 1 mLof 2.5 N NaOH. The reaction was maintained overnight at ambienttemperature. LC-MS analysis showed the reaction was complete with thephenol acid as the major product. Purification by mass-directedreverse-phase prep HPLC (0-40% AcCN/H₂O, 0.1% TFA) and subsequentlyophilization afforded 12 mg (41%) of Compound 15 as a fluffy, whitesolid (TFA salt). ¹H NMR: δ_(H) (400 MHz, CD₃OD): 7.05 (d, 1H), 6.78 (d,1H), 6.68 (dd, 1H), 4.32 (q, 1H), 3.99 (d, 1H), 3.38-3.32 (m, 2H),3.28-3.13 (m, 3H), 3.05 (dd, 1H), 3.00-2.85 (m, 2H), 2.68 (ddd, 1H),2.60-2.48 (m, 2H), 2.12 (dd, 1H), 1.88 (dd, 1H), 1.72 (app t, 1H),1.45-1.30 (m, 4H), 1.18-1.05 (m, 1H), 0.88-0.80 (m, 1H), 0.80-0.70 (m,1H), 0.55-0.45 (m, 2H). LC/MS, m/z=457.2 [M+H]⁺ (Calc: 457.56).

Example 8 Synthesis of(S)-1-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetyl)pyrrolidine-2-carboxylicacid (Compound 16)

Compound 16 was prepared from Compound 8 in a similar manner asdescribed in EXAMPLE 6 employing (S)-methyl pyrrolidine-2-carboxylatehydrochloride in the initial amide coupling step. Compound 16 wasobtained after purification by reverse-phase preparative HPLC (0-60%AcCN/H₂O, 0.1% TFA) and subsequent lyophilization to give 46 mg (28%) asa fluffy, white solid (TFA salt). ¹H NMR: δ_(H) (400 MHz, CD₃OD): 7.15(d, 1H), 6.89 (d, 1H), 6.83 (dd, 1H), 4.38 (dd, 1H), 4.01 (d, 1H), 3.76(s, 3H), 3.63-3.40 (m, 3H), 3.40-3.30 (m, 2H), 3.28-3.15 (m, 2H),3.10-3.02 (m, 1H), 3.10-2.90 (m, 2H), 2.75-2.50 (m, 3H), 2.30-2.17 (m,1H), 2.13 (dd, 1H), 2.05-1.90 (m, 4H), 1.71 (app t, 1H), 1.42 (d, 1H),1.18-1.05 (m, 1H), 0.88-0.80 (m, 1H), 0.80-0.70 (m, 1H), 0.55-0.45 (m,2H). LC/MS, m/z=497.3 [M+H]⁺ (Calc: 497.60).

Example 9 Synthesis of(S)-1-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetyl)pyrrolidine-2-carboxylicacid (Compound 17)

To a 0° C. solution of Compound 16 (0.040 g, 0.081 mmol) from EXAMPLE 8in 3 mL of anhydrous CH₂Cl₂ was added a 1.0 M solution of BBr₃ in CH₂Cl₂(0.400 mL, 0.400 mmol) dropwise via syringe. The resulting yellowsuspension was maintained at 0° C. for 2 h. LC-MS showed that thereaction was mostly complete. The reaction was quenched with 5 mL ofMeOH and stirred at ambient temperature for 1 h. The solution wasconcentrated then redissolved in 3 mL of MeOH and treated with 1 mL of2.5 N NaOH. The reaction was maintained overnight at ambienttemperature. LC-MS analysis showed the reaction was complete with thephenol acid as the major product. Purification by mass-directedreverse-phase prep HPLC (0-60% AcCN/H₂O, 0.1% TFA) and subsequentlyophilization afforded 17 mg (44%) of Compound 17 as a fluffy, whitesolid (TFA salt). ¹H NMR: δ_(H) (400 MHz, CD₃OD): 7.05 (d, 1H), 6.78 (d,1H), 6.68 (dd, 1H), 4.39 (dd, 1H), 3.99 (d, 1H), 3.63-3.40 (m, 3H),3.40-3.30 (m, 2H), 3.27-3.12 (m, 3H), 3.04 (dd, 1H), 3.08-2.85 (m, 2H),2.75-2.62 (m, 2H), 2.62-2.50 (m, 1H), 2.30-2.17 (m, 1H), 2.12 (dd, 1H),2.03-1.90 (m, 4H), 1.74 (app t, 1H), 1.38 (d, 1H), 1.17-1.05 (m, 1H),0.88-0.80 (m, 1H), 0.80-0.70 (m, 1H), 0.58-0.45 (m, 2H). LC/MS,m/z=483.3 [M+H]⁺ (Calc: 483.57).

Example 10 Synthesis of(S)-2-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamido)-4-methylpentanoicacid (Compound 18)

Compound 18 was prepared from Compound 8 in a similar manner asdescribed in EXAMPLE 6 employing (S)-methyl 2-amino-4-methylpentanoatehydrochloride in the initial amide coupling step. Compound 18 wasobtained after purification by reverse-phase preparative HPLC (0-60%AcCN/H₂O, 0.1% TFA) and subsequent lyophilization to give 89 mg (46%) asa fluffy, white solid. ¹H NMR: δ_(H) (400 MHz, CD₃OD): 8.18 (d, 1H),7.15 (d, 1H), 6.89 (d, 1H), 6.83 (dd, 1H), 4.42-4.30 (m, 1H), 4.01 (d,1H), 3.76 (s, 3H), 3.42-3.32 (m, 3H), 3.27-3.15 (m, 2H), 3.05 (dd, 1H),3.02-2.90 (m, 2H), 2.72-2.47 (m, 3H), 2.12 (dd, 1H), 1.88 (dd, 1H),1.80-1.65 (m, 2H), 1.63-1.50 (m, 2H), 1.42 (d, 1H), 1.18-1.05 (m, 1H),0.94 (d, 3H), 0.90 (d, 3H), 0.87-0.80 (m, 1H), 0.80-0.70 (m, 1H),0.67-0.45 (m, 2H). LC/MS, m/z=513.3 [M+H]⁺ (Calc: 513.64).

Example 11 Synthesis of(S)-2-(2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamido)-4-methylpentanoicacid (Compound 19)

To a 0° C. solution of Compound 18 (0.074 g, 0.144 mmol) from EXAMPLE 10in 4 mL of anhydrous CH₂Cl₂ was added a 1.0 M solution of BBr₃ in CH₂Cl₂(0.722 mL, 0.722 mmol) dropwise via syringe. The resulting yellowsuspension was maintained at 0° C. for 1.25 h. LC-MS showed that thereaction was mostly complete. The reaction was quenched with 5 mL ofMeOH and maintained for 1 h at ambient temperature. The solution wasconcentrated then redissolved in 3 mL of MeOH and treated with 1 mL of2.5 N NaOH. The reaction was maintained overnight at ambienttemperature. LC-MS analysis showed the reaction was complete with thephenol acid as the major product. Purification by mass-directedreverse-phase preparative HPLC (0-60% AcCN/H₂O, 0.1% TFA) and subsequentlyophilization afforded 42 mg (58%) of Compound 19 as a fluffy, whitesolid (TFA salt). ¹H NMR: δ_(H) (400 MHz, CD₃OD): 8.19 (d, 1H), 7.05 (d,1H), 6.78 (d, 1H), 6.68 (dd, 1H), 4.43-4.30 (m, 1H), 3.99 (d, 1H),3.40-3.30 (m, 2H), 3.25-3.12 (m, 2H), 3.05 (dd, 1H), 3.00-2.85 (m, 2H),2.68 (ddd, 1H), 2.60-2.48 (m, 2H), 2.11 (dd, 1H), 1.89 (dd, 1H),1.80-1.67 (m, 2H), 1.65-1.50 (m, 2H), 1.38 (d, 1H), 1.18-1.05 (m, 1H),0.94 (d, 3H), 0.90 (d, 3H), 0.88-0.80 (m, 1H), 0.80-0.70 (m, 1H),0.57-0.45 (m, 2H). LC/MS, m/z=499.2 [M+H]⁺ (Calc: 499.61).

Example 12 Synthesis of(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-7-isobutoxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 23)

DIPEA (13.3 mL, 76 mmol) was added to Compound 7 (27.4 g, 72.5 mmol) inAc₂O (68.4 mL, 725 mmol) and the solution was heated at 120° C. for 2 h.The reaction mixture was diluted with EtOAc, and the mixture washed withsatd. aq. NaHCO₃ (2×), dried over Na₂SO₄, and dried under vacuum. ACN(300 mL) and 4-acetamidobenzenesulfonyl azide (34.8 g, 145 mmol,Compound 20) were added, followed by DBU (32.8 mL, 218 mmol) at 0° C.The reaction was allowed to warm to RT over 18 h and concentrated. EtOAcwas added, washed with two portions of 1M aq. NaOH, dried over Na₂SO₄and concentrated. The resulting brown solid was triturated with acetone,filtered and concentrated to give 17.28 g of Compound 21 as a yellowsolid which was used in subsequent steps without further purification.LC/MS, m/z=410 [M+H]⁺ (Calc: 409).

A solution of Compound 21 (409 mg, 1 mmol) in DCE (3 mL) was addeddropwise to 2-methyl-1-propanol (0.11 mL, 1.2 mmol) and rhodium(II)acetate dimer (8 mg, 0.02 mmol) in DCE (2 mL) at 80° C. The solution wasstirred at 80° C. for 45 min, concentrated, and purified by MPLC (SiO₂,0-50% acetone/hexanes) to give 380 mg of Compound 22 as a clear oil.LC/MS, m/z=456 [M+H]⁺ (Calc: 455).

To a solution of Compound 22 (380 mg, 0.83 mmol) in MeOH (3 mL) wasadded 2.5 M aq. NaOH (1.2 mL, 3 mmol) and the solution was heated at 80°C. for 75 min. EtOAc was added, and the mixture washed with satd. aq.NaHCO₃, dried over Na₂SO₄ and concentrated to yield crude product.Purification by reverse-phase prep HPLC (C18, 0-60% 0.1% TFA in ACN/0.1%TFA in water) gave Compound 23 as its TFA salt. ¹H NMR δ_(H) (400 MHz,DMSO-d₆): 8.92 (br. s., 1H), 7.05 (d, J=8.4 Hz, 1H), 6.75-6.85 (m, 2H),6.53 (s, 1H), 4.22 (dd, J=12.1, 6.8 Hz, 1H), 3.86 (d, J=5.9 Hz, 1H),3.66 (s, 3H), 3.22-3.38 (m, 3H), 3.07-3.16 (m, 1H), 2.90-3.02 (m, 3H),2.89-2.76 (m, 2H), 2.18-2.39 (m, 3H), 1.56-1.70 (m, 1H), 1.52 (t, J=12.7Hz, 1H), 1.30 (d, J=12.3 Hz, 1H), 0.93-1.05 (m, 1H), 0.73 (d, J=1.5 Hz,3H), 0.72 (d, J=1.5 Hz, 3H), 0.59-0.67 (m, 1H), 0.50-0.58 (m, 1H),0.38-0.46 (m, 1H), 0.31-0.38 (m, 1H). LC/MS, m/z=414 [M+H]⁺ (Calc: 413).

In a similar manner, the following compounds were prepared:

(4bR,7S,8aS,9R)-7-(benzyloxy)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt (Compound 24): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 8.92 (br. s.,1H), 7.28-7.17 (m, 5H), 7.05 (d, J=8.6 Hz, 1H), 6.85 (d, J=2.6 Hz, 1H),6.79 (dd, J=8.4, 2.4 Hz, 1H), 6.52 (s, 1H), 4.59 (d, J=12.1 Hz, 1H),4.39 (dd, J=12.0, 6.9 Hz, 1H), 4.33 (d, J=12.1 Hz, 1H), 3.87 (d, J=5.9Hz, 1H), 3.67 (s, 3H), 3.33-3.23 (m, 2H), 3.11 (dd, J=20.5, 7.3 Hz, 1H),3.03-2.88 (m, 3H), 2.86-2.77 (m, 1H), 2.40-2.20 (m, 3H), 1.59 (t, J=12.7Hz, 1H), 1.32 (d, J=12.5 Hz, 1H), 1.05-0.94 (m, 1H), 0.67-0.58 (m, 1H),0.58-0.50 (m, 1H), 0.45-0.38 (m, 1H), 0.38-0.30 (m, 1H). LC/MS, m/z=448[M+H]⁺ (Calc: 447); and

(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-7,8a-dihydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 25) (which was produced as a byproduct duringpreparation of Compound 24): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 8.95 (br.s., 1H), 7.18 (d, J=8.6 Hz, 0.4H), 7.15-7.10 (m, 1H), 6.95-6.88 (m, 1H),6.85 (dd, J=8.5, 2.3 Hz, 0.6H), 6.50 (s, 0.6H), 6.33 (s, 0.4H), 4.42(dd, J=11.9, 7.0 Hz, 0.6H), 3.93-3.85 (m, 1.6H), 3.78 (s, 1.6H), 3.73(s, 2H), 3.41-3.26 (m, 3.6H), 3.18 (d, J=6.8 Hz, 1.6H), 3.05-2.94 (m,2.5H), 2.92-2.81 (m, 1.2H), 2.74 (dd, J=13.3, 6.1 Hz, 0.5H), 2.46-2.17(m, 3.2H), 2.11 (t, J=12.9 Hz, 0.4H), 1.58 (t, J=12.7 Hz, 0.6H),1.44-1.33 (m, 1H), 1.13-0.98 (m, 1H), 0.74-0.55 (m, 2H), 0.54-0.36 (m,2H). LC/MS, m/z=358 [M+H]⁺ (Calc: 357).

Example 13 Synthesis ofN-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)isobutyramide(TFA salt) (Compound 26) andN-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)isobutyramide(TFA salt) (Compound 27)

A solution of Compound 21 (500 mg, 1.2 mmol) in DCE (2 mL) was addeddropwise to isobutyramide (177 mg, 1.34 mmol) and rhodium(II) acetatedimer (11 mg, 0.02 mmol) in DCE (2 mL) at 80° C. The solution wasstirred at 80° C. for 90 min. then concentrated. MeOH (2 mL) was addedfollowed by 2.5 M aq. NaOH (1.5 mL, 3.7 mmol) and the resulting solutionstirred at RT for 72 h. DCM was added followed by satd. aq. NaHCO₃ andthe mixture was passed through a phase separation column (BiotageIsolute 120-1906-D). Concentration followed by purification by MPLC(SiO₂, 0-60% acetone/hexanes) and reverse-phase prep HPLC (C18, 0-60%0.1% TFA in ACN/0.1% TFA in water) gave Compound 26 as its TFA salt. ¹HNMR δ_(H) (400 MHz, DMSO-d₆): 8.96 (br. s., 1H), 7.73 (d, J=8.6 Hz, 1H),7.06 (d, J=8.6 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.77 (dd, J=8.4, 2.4 Hz,1H), 6.56 (s, 1H), 4.90-4.81 (m, 1H), 3.89 (d, J=5.9 Hz, 1H), 3.66 (s,3H), 3.35-3.23 (m, 2H), 3.06 (dd, J=19.7, 6.3 Hz, 1H), 2.99 (d, J=2.2Hz, 2H), 2.94 (d, J=8.1 Hz, 1H), 2.85-2.77 (m, 1H), 2.39-2.22 (m, 3H),2.10 (dd, J=13.3, 6.5 Hz, 1H), 1.64 (t, J=13.0 Hz, 1H), 1.31 (d, J=10.3Hz, 1H), 1.03-0.95 (m, 1H), 0.89 (d, J=6.8 Hz, 3H), 0.85 (d, J=6.8 Hz,3H), 0.66-0.58 (m, 1H), 0.58-0.50 (m, 1H), 0.45-0.30 (m, 2H). LC/MS,m/z=427 [M+H]⁺ (Calc: 426).

A 1 M solution of BBr₃ in DCM (2.9 mL, 2.9 mmol) was added slowly toCompound 26 (308 mg, 0.72 mmol) in DCM (2 mL). The solution was stirredat RT for 90 min. then slowly quenched with 1.6 mL of 7 M NH₃ in MeOH(11.5 mmol). The resulting salts were filtered off and the filtratepurified by MPLC (SiO₂, 0-20% (10% NH₄OH/MeOH)/DCM) followed byreverse-phase prep HPLC (C18, 0-60% 0.1% TFA in ACN/0.1% TFA in water)to give Compound 27 as its TFA salt. ¹H NMR δ_(H) (400 MHz, DMSO-d₆):9.40 (br. s., 1H), 8.99 (br. s., 1H), 7.82 (d, J=8.6 Hz, 1H), 7.00 (d,J=8.4 Hz, 1H), 6.75 (d, J=2.2 Hz, 1H), 6.65 (dd, J=8.3, 2.3 Hz, 1H),6.59 (s, 1H), 4.96-4.87 (m, 1H), 3.94 (d, J=5.9 Hz, 1H), 3.41-3.26 (m,2H), 3.13-2.96 (m, 3H), 2.94-2.82 (m, 2H), 2.47-2.29 (m, 3H), 2.16 (dd,J=13.2, 6.4 Hz, 1H), 1.75 (t, J=13.0 Hz, 1H), 1.34 (d, J=11.4 Hz, 1H),1.10-1.01 (m, 1H), 0.97 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H),0.72-0.65 (m, 1H), 0.65-0.56 (m, 1H), 0.56-0.44 (m, 1H), 0.44-0.33 (m,1H). LC/MS, m/z=413 [M+H]⁺ (Calc: 412).

In a similar manner, the following compounds were prepared:

N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamide(Compound 28): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.33 (br. s., 1H), 8.91(br. s., 1H), 7.87 (d, J=8.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.68 (d,J=2.4 Hz, 1H), 6.57 (dd, J=8.3, 2.3 Hz, 1H), 6.53 (s, 1H), 4.83 (dt,J=12.8, 7.5 Hz, 1H), 3.86 (d, J=5.9 Hz, 1H), 3.33-3.19 (m, 2H),3.06-2.96 (m, 2H), 2.92 (d, J=10.1 Hz, 1H), 2.86-2.73 (m, 2H), 2.38-2.22(m, 2H), 2.11 (dd, J=13.2, 6.6 Hz, 1H), 1.70 (s, 3H), 1.63 (t, J=13.0Hz, 1H), 1.27 (d, J=11.9 Hz, 1H), 0.98 (d, J=4.8 Hz, 1H), 0.66-0.58 (m,1H), 0.58-0.48 (m, 1H), 0.48-0.26 (m, 2H). LC/MS, m/z=385 [M+H]⁺ (Calc:384);

N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)propionamide(Compound 29): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.40 (br. s., 1H), 8.99(br. s., 1H), 7.85 (d, J=8.4 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.75 (d,J=2.2 Hz, 1H), 6.65 (dd, J=8.4, 2.2 Hz, 1H), 6.60 (s, 1H), 4.96-4.87 (m,1H), 3.93 (d, J=5.9 Hz, 1H), 3.39-3.28 (m, 2H), 3.14-2.96 (m, 3H),2.92-2.82 (m, 2H), 2.47-2.31 (m, 2H), 2.18 (dd, J=13.3, 6.5 Hz, 1H),2.11-1.98 (m, 2H), 1.72 (t, J=13.1 Hz, 1H), 1.34 (d, J=11.7 Hz, 1H),1.12-1.01 (m, 1H), 0.95 (t, J=7.6 Hz, 3H), 0.72-0.57 (m, 2H), 0.52-0.36(m, 2H). LC/MS, m/z=399 [M+H]⁺ (Calc: 398);

N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-4-methylpentanamide(Compound 30): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.39 (s, 1H), 8.98 (br.s., 1H), 7.88 (d, J=8.6 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.75 (d, J=2.2Hz, 1H), 6.65 (dd, J=8.3, 2.3 Hz, 1H), 6.59 (s, 1H), 4.97-4.87 (m, 1H),3.93 (d, J=5.7 Hz, 1H), 3.40-3.28 (m, 2H), 3.13-2.96 (m, 3H), 2.91-2.82(m, 2H), 2.46-2.31 (m, 2H), 2.16 (dd, J=13.0, 6.4 Hz, 1H), 2.03 (t,J=7.7 Hz, 2H), 1.72 (t, J=13.0 Hz, 1H), 1.46 (dquin, J=13.2, 6.6 Hz,1H), 1.38-1.30 (m, 3H), 1.10-1.02 (m, 1H), 0.83 (d, J=1.8 Hz, 3H), 0.81(d, J=2.0 Hz, 3H), 0.72-0.57 (m, 2H), 0.51-0.44 (m, 1H), 0.44-0.38 (m,1H). LC/MS, m/z=441 [M+H]⁺ (Calc: 440);

N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-5-methylhexanamide(Compound 31): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.40 (s, 1H), 8.98 (br.s., 1H), 7.87 (d, J=8.6 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.75 (d, J=2.2Hz, 1H), 6.65 (dd, J=8.3, 2.3 Hz, 1H), 6.59 (s, 1H), 4.97-4.88 (m, 1H),3.93 (d, J=5.7 Hz, 1H), 3.39-3.28 (m, 2H), 3.12-2.96 (m, 3H), 2.92-2.81(m, 2H), 2.45-2.30 (m, 2H), 2.16 (dd, J=13.2, 6.4 Hz, 1H), 2.01 (t,J=7.0 Hz, 2H), 1.73 (t, J=13.0 Hz, 1H), 1.53-1.39 (m, 3H), 1.34 (d,J=11.9 Hz, 1H), 1.15-1.00 (m, 3H), 0.83 (d, J=0.9 Hz, 3H), 0.82 (d,J=1.1 Hz, 3H), 0.72-0.57 (m, 2H), 0.52-0.36 (m, 2H). LC/MS, m/z=455[M+H]⁺ (Calc: 454);

N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)pivalamide(Compound 32): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.31 (s, 1H), 8.91 (br.s., 1H), 7.34 (d, J=8.6 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.68 (d, J=2.2Hz, 1H), 6.58 (dd, J=8.1, 2.2 Hz, 1H), 6.47 (s, 1H), 4.96-4.84 (m, 1H),3.85 (d, J=5.7 Hz, 1H), 3.32-3.20 (m, 2H), 3.05-2.89 (m, 3H), 2.88-2.75(m, 2H), 2.40-2.23 (m, 2H), 2.05-1.98 (m, 1H), 1.89 (t, J=12.8 Hz, 1H),1.25 (d, J=11.2 Hz, 1H), 1.04-0.93 (m, 10H), 0.66-0.58 (m, 1H),0.57-0.50 (m, 1H), 0.45-0.29 (m, 2H). LC/MS, m/z:=427 [M+H]⁺ (Calc:426);

N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-3-methylbutanamide(Compound 33): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.33 (br. s., 1H), 8.92(br. s., 1H), 7.80 (d, J=8.6 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.68 (d,J=2.2 Hz, 1H), 6.58 (dd, J=8.3, 2.3 Hz, 1H), 6.53 (s, 1H), 4.93-4.82 (m,1H), 3.87 (d, J=5.9 Hz, 1H), 3.33-3.20 (m, 2H), 3.08-2.89 (m, 3H),2.87-2.73 (m, 2H), 2.38-2.24 (m, 2H), 2.09 (dd, J=13.2, 6.4 Hz, 1H),1.90-1.79 (m, 3H), 1.67 (t, J=13.0 Hz, 1H), 1.27 (d, J=11.7 Hz, 1H),1.05-0.93 (m, 1H), 0.79 (d, J=6.8 Hz, 3H), 0.75 (d, J=6.4 Hz, 3H),0.65-0.50 (m, 2H), 0.44-0.30 (m, 2H). LC/MS, m/z=427 [M+H]⁺ (Calc: 426);

N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)cyclopropanecarboxamide(Compound 34): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.34 (br. s., 1H), 8.91(br. s., 1H), 8.11 (d, J=8.6 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.69 (d,J=2.2 Hz, 1H), 6.58 (dd, J=8.3, 2.3 Hz, 1H), 6.52 (s, 1H), 4.93-4.84 (m,1H), 3.86 (d, J=5.9 Hz, 1H), 3.34-3.17 (m, 2H), 3.10-2.89 (m, 3H),2.86-2.74 (m, 2H), 2.38-2.23 (m, 2H), 2.12 (dd, J=13.2, 6.4 Hz, 1H),1.66 (t, J=12.9 Hz, 1H), 1.48 (quin, J=6.3 Hz, 1H), 1.27 (d, J=11.9 Hz,1H), 1.04-0.93 (m, 1H), 0.64-0.49 (m, 6H), 0.44-0.28 (m, 2H). LC/MS,m/z=411 [M+H]⁺ (Calc: 410);

N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)cyclopentanecarboxamide(Compound 35): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.32 (br. s., 1H), 8.91(br. s., 1H), 7.76 (d, J=8.6 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.68 (d,J=2.0 Hz, 1H), 6.58 (dd, J=8.3, 2.3 Hz, 1H), 6.51 (s, 1H), 4.92-4.81 (m,1H), 3.86 (d, J=5.7 Hz, 1H), 3.33-3.19 (m, 2H), 3.06-2.88 (m, 3H),2.85-2.74 (m, 2H), 2.51-2.45 (m, 1H), 2.38-2.24 (m, 2H), 2.09 (dd,J=13.3, 6.5 Hz, 1H), 1.74-1.33 (m, 9H), 1.26 (d, J=11.7 Hz, 1H),1.04-0.93 (m, 1H), 0.66-0.58 (m, 1H), 0.58-0.49 (m, 1H), 0.45-0.29 (m,2H). LC/MS, m/z=439 [M+H]⁺ (Calc: 438);

N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)benzamide(Compound 36): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.33 (s, 1H), 8.95 (br.s., 1H), 8.37 (d, J=8.4 Hz, 1H), 7.76 (d, J=7.3 Hz, 2H), 7.48-7.41 (m,1H), 7.40-7.32 (m, 2H), 6.96 (d, J=8.4 Hz, 1H), 6.70 (d, J=2.2 Hz, 1H),6.63-6.56 (m, 2H), 5.16-5.05 (m, 1H), 3.89 (d, J=5.9 Hz, 1H), 3.35-3.23(m, 2H), 3.09-2.76 (m, 5H), 2.40-2.25 (m, 2H), 2.14 (dd, J=13.6, 6.4 Hz,1H), 2.03 (t, J=13.6 Hz, 1H), 1.29 (d, J=11.0 Hz, 1H), 1.07-0.95 (m,1H), 0.66-0.58 (m, 1H), 0.58-0.51 (m, 1H), 0.46-0.38 (m, 1H), 0.38-0.30(m, 1H). LC/MS, m/z=447 [M+H]⁺ (Calc: 446);

(S)—N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-2-methylbutanamide(Compound 37): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.33 (br. s., 1H), 8.92(br. s., 1H), 7.77 (d, J=8.6 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.68 (d,J=2.0 Hz, 1H), 6.58 (dd, J=8.4, 2.2 Hz, 1H), 6.52 (s, 1H), 4.88 (dd,J=13.0, 7.5 Hz, 1H), 3.86 (d, J=5.9 Hz, 2H), 3.33-3.21 (m, 2H),3.07-2.89 (m, 3H), 2.87-2.75 (m, 2H), 2.40-2.23 (m, 3H), 2.14-2.01 (m,2H), 1.70 (t, J=0.7 Hz, 1H), 1.45-1.32 (m, 1H), 1.27 (d, J=11.4 Hz, 1H),1.23-1.08 (m, 1H), 1.03-0.94 (m, 1H), 0.84 (d, J=6.8 Hz, 3H), 0.75 (t,J=7.5 Hz, 3H), 0.65-0.57 (m, 1H), 0.57-0.49 (m, 1H), 0.45-0.29 (m, 2H).LC/MS, m/z=427 [M+H](Calc: 426);

N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)cyclohexanecarboxamide(Compound 38): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.32 (br. s., 1H), 8.91(br. s., 1H), 7.68 (d, J=8.6 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.67 (d,J=2.2 Hz, 1H), 6.58 (dd, J=8.3, 2.3 Hz, 1H), 6.50 (s, 1H), 4.89-4.78 (m,1H), 3.85 (d, J=5.9 Hz, 1H), 3.33-3.20 (m, 2H), 3.05-2.89 (m, 3H),2.83-2.74 (m, 2H), 2.38-2.23 (m, 2H), 2.11-1.96 (m, 2H), 1.68 (t, J=13.0Hz, 2H), 1.63-1.45 (m, 5H), 1.29-0.93 (m, 7H), 0.65-0.58 (m, 1H),0.58-0.49 (m, 1H), 0.45-0.29 (m, 2H). LC/MS, m/z=453 [M+H]⁺ (Calc: 452);

N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamide(TFA salt) (Compound 97): ¹H NMR (DMSO-d₆) δ: 9.34 (s, 1H), 9.23 (br.s., 1H), 7.87 (d, J=8.6 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.67 (d, J=2.0Hz, 1H), 6.57 (dd, J=8.1, 2.2 Hz, 1H), 6.44 (s, 1H), 4.88-4.74 (m, 1H),3.51 (d, J=5.7 Hz, 1H), 3.26 (d, J=19.8 Hz, 1H), 3.03-2.90 (m, 3H), 2.80(d, J=13.9 Hz, 1H), 2.76 (d, J 4.6 Hz, 3H), 2.43-2.31 (m, 1H), 2.30-2.19(m, 1H), 2.04 (dd, J=13.2, 6.4 Hz, 1H), 1.70 (s, 3H), 1.62 (t, J=13.0Hz, 1H), 1.26 (d, J=12.5 Hz, 1H). LC/MS, m/z=345.2 [M+H]⁺ (Calc: 344.4);

N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)propionamide(TFA salt) (Compound 98): ¹H NMR (DMSO-d₆) δ: 9.33 (s, 1H), 9.22 (br.s., 1H), 7.78 (d, J=8.6 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.67 (d, J=2.0Hz, 1H), 6.57 (dd, J=8.3, 2.1 Hz, 1H), 6.43 (s, 1H), 4.88-4.76 (m, 1H),3.51 (d, J=6.2 Hz, 1H), 3.27-3.23 (m, 1H), 3.04-2.90 (m, 3H), 2.80 (d,J=13.9 Hz, 1H), 2.76 (d, J=4.8 Hz, 3H), 2.43-2.31 (m, 1H), 2.29-2.17 (m,1H), 2.08-1.91 (m, 3H), 1.64 (t, J=13.1 Hz, 1H), 1.26 (d, J=13.2 Hz,1H), 0.87 (t, J=7.6 Hz, 3H). LC/MS, m/z=359.2 [M+H]⁺ (Calc: 358.43);

N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)isobutyramide(TFA salt) (Compound 99): ¹H NMR (DMSO-d₆) δ: 9.33 (s, 1H), 9.23 (br.s., 1H), 7.74 (d, J=8.6 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.67 (d, J=2.2Hz, 1H), 6.58 (dd, J=8.3, 2.1 Hz, 1H), 6.41 (s, 1H), 4.86-4.75 (m, 1H),3.50 (d, J=5.7 Hz, 1H), 3.28-3.20 (m, 1H), 3.02-2.90 (m, 3H), 2.79 (d,J=14.1 Hz, 1H), 2.76 (d, J=4.6 Hz, 3H), 2.39-2.30 (m, 1H), 2.30-2.18 (m,2H), 2.01 (dd, J=13.2, 6.4 Hz, 1H), 1.67 (t, J=13.1 Hz, 1H), 1.26 (d,J=13.0 Hz, 1H), 0.90 (d, J=6.8 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H). LC/MS,m/z=373.4 [M+H]⁺ (Calc: 372.46);

N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)pivalamide(TFA salt) (Compound 100): ¹H NMR (DMSO-d₆) δ: 9.33 (s, 1H), 9.23 (br.s., 1H), 7.33 (d, J=8.6 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.67 (d, J=2.2Hz, 1H), 6.58 (dd, J-8.3, 2.1 Hz, 1H), 6.37 (s, 1H), 4.85 (dt, J=12.5,7.7 Hz, 1H), 3.50 (d, J=5.3 Hz, 1H), 3.28-3.21 (m, 1H), 3.00-2.88 (m,3H), 2.82-2.73 (m, 4H), 2.40-2.18 (m, 2H), 1.98-1.83 (m, 2H), 1.24 (d,J=12.5 Hz, 1H), 0.98 (s, 9H). LC/MS, m/z=387.2 [M+H]⁺ (Calc: 386.48);

N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-4-methylpentanamide(TFA salt) (Compound 101): ¹H NMR (DMSO-d₆) δ: 9.34 (s, 1H), 9.23 (br.s., 1H), 7.80 (d, J=8.6 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.67 (d, J=2.2Hz, 1H), 6.58 (dd, J=8.1, 2.2 Hz, 1H), 6.43 (s, 1H), 4.87-4.75 (m, 1H),3.51 (d, J=5.5 Hz, 1H), 3.28-3.20 (m, 1H), 3.03-2.89 (m, 3H), 2.79 (d,J=13.9 Hz, 1H), 2.76 (d, J=4.8 Hz, 3H), 2.40-2.30 (m, 1H), 2.29-2.19 (m,1H), 2.04-1.91 (m, 3H), 1.65 (t, J=13.1 Hz, 1H), 1.39 (dquin, J=13.3,6.7 Hz, 1H), 1.31-1.21 (m, 3H), 0.76 (d, J=1.5 Hz, 3H), 0.74 (d, J=1.5Hz, 3H). LC/MS, m/z=401.4 [M+H]⁺ (Calc: 400.51);

N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-5-methylhexanamide(TFA salt) (Compound 102): ¹H NMR (DMSO-d₆) δ: 9.34 (s, 1H), 9.23 (br.s., 1H), 7.79 (d, J=8.6 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.67 (d, J=2.0Hz, 1H), 6.57 (dd, J=8.3, 2.1 Hz, 1H), 6.43 (s, 1H), 4.88-4.77 (m, 1H),3.51 (d, J=5.9 Hz, 1H), 3.28-3.20 (m, 1H), 3.02-2.91 (m, 3H), 2.79 (d,J=13.9 Hz, 1H), 2.76 (d, J=4.8 Hz, 3H), 2.41-2.31 (m, 1H), 2.30-2.19 (m,1H), 2.01 (dd, J=13.2, 6.4 Hz, 1H), 1.96-1.90 (m, 2H), 1.65 (t, J=13.0Hz, 1H), 1.46-1.31 (m, 3H), 1.26 (d, J=13.0 Hz, 1H), 1.08-0.95 (m, 2H),0.76 (d, J=0.9 Hz, 3H), 0.74 (d, J=0.9 Hz, 3H). LC/MS, m/z=415.4 [M+H]⁺(Calc: 414.54);

N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)cyclohexanecarboxamide(TFA salt) (Compound 103): ¹H NMR (DMSO-d₆) δ: 9.34 (s, 1H), 9.24 (br.s., 1H), 6.95 (d, J=8.4 Hz, 1H), 6.66 (d, J=2.2 Hz, 1H), 6.58 (dd,J=8.4, 2.2 Hz, 1H), 6.41 (s, 1H), 4.85-4.75 (m, 1H), 3.51 (d, J=5.7 Hz,1H), 3.26 (d, J=18.5 Hz, 1H), 3.00-2.89 (m, 3H), 2.81-2.73 (m, 4H),2.41-2.31 (m, 1H), 2.31-2.19 (m, 1H), 2.05-1.93 (m, 2H), 1.72-1.63 (m,1H), 1.63-1.46 (m, 5H), 1.28-1.16 (m, 3H), 1.16-1.00 (m, 3H). LC/MS,m/z=413.4 [M+H]⁺ (Calc: 412.52);

N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)piperidine-4-carboxamide(TFA salt) (Compound 109): ¹H NMR (DMSO-d₆) δ: 9.40 (s, 1H), 8.99 (br.s., 1H), 8.55-8.45 (m, 1H), 8.29-8.15 (m, 1H), 8.01 (d, J=8.6 Hz, 1H),7.00 (d, J=8.4 Hz, 1H), 6.74 (d, J=2.2 Hz, 1H), 6.65 (dd, J=8.4, 2.2 Hz,1H), 6.59 (s, 1H), 4.95-4.85 (m, 1H), 3.93 (d, J=5.9 Hz, 1H), 3.40-3.19(m, 3H), 3.12-2.97 (m, 3H), 2.93-2.73 (m, 5H), 2.45-2.29 (m, 3H), 2.16(dd, J=13.2, 6.6 Hz, 1H), 1.87-1.59 (m, 6H), 1.34 (d, J=11.4 Hz, 1H),1.12-1.01 (m, 1H), 0.74-0.64 (m, 1H), 0.64-0.56 (m, 1H), 0.53-0.45 (m,1H), 0.45-0.36 (m, 1H). LC/MS, m/z=454 [M+H]⁺ (Calc: 453); and

N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-2-(dimethylamino)acetamide(TFA salt) (Compound 110): ¹H NMR (DMSO-d₆) δ: 9.72 (br. s., 1H), 9.44(br. s., 1H), 9.03 (br. s., 1H), 8.68 (d, J=8.1 Hz, 1H), 7.01 (d, J=8.4Hz, 1H), 6.75 (d, J=2.2 Hz, 2H), 6.66 (dd, J=8.4, 2.2 Hz, 1H), 4.99-4.85(m, 1H), 3.97 (d, J=5.9 Hz, 1H), 3.86 (s, 2H), 3.41-3.29 (m, 2H),3.17-2.84 (m, 5H), 2.77 (s, 6H), 2.46-2.32 (m, 2H), 2.26 (dd, J=13.1,6.5 Hz, 1H), 1.75 (t, J=13.0 Hz, 1H), 1.36 (d, J=12.1 Hz, 1H), 1.11-1.00(m, 1H), 0.74-0.65 (m, 1H), 0.65-0.57 (m, 1H), 0.54-0.35 (m, 2H). LC/MS,m/z=428 [M+H]⁺ (Calc: 427).

Example 14 Synthesis ofN-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)ethanesulfonamideTFA salt (Compound 42)

A solution of Compound 21 (4.47 g, 10.8 mmol) in DCE (24 mL) was addeddropwise to O-t-butyl carbamate (1.52 g, 13 mmol) and rhodium(II)acetate dimer (95 mg, 0.216 mmol) in DCE (24 mL) at 80° C. The solutionwas stirred at 80° C. for 15 min, then concentrated. Purification byMPLC (SiO₂, 0-40% acetone/hexanes) gave 3.75 g of Compound 39 as a whitefoam. LC/MS, m/z=499 [M+H]⁺ (Calc: 498).

MeOH (50 mL) was added to Compound 39 (3.75 g, 7.5 mmol) followed by 7 MNH₃ in MeOH (0.77 mL, 5.4 mmol). The solution was heated at reflux for19 h then concentrated. DCM (45 mL) was added followed by TFA (10 mL)and the solution was stirred at RT for 40 min then concentrated. Theresulting material was subjected to the following sequence three times:the material was taken up in 25 mL DCM, 2 M HCl in Et₂O (25 mL, 50 mmol)added and the solution briefly swirled then concentrated. Final dryingunder vacuum gave 4.60 g of Compound 40 (2 HCl salt) as a brown foam.LC/MS, m/z=357 [M+H]⁺ (Calc: 356).

DIPEA (0.49 mL, 2.8 mmol) was added slowly to Compound 40 (2 HCl salt)(400 mg, 0.9 mmol) and ethanesulfonyl chloride (0.11 mL, 1.1 mmol) inDCM (2 mL) and the resulting solution was stirred at RT for 2 h. DCM wasadded followed by 10% aq. NH₄OH and the mixture was passed through aphase separation column (Biotage Isolute 120-1906-D). Concentration andpurification by MPLC (SiO₂, 0-10% MeOH/DCM) gave 223 mg of Compound 41.LC/MS, m/z=449 [M+H]⁺ (Calc: 448).

A 1 M solution of BBr₃ in DCM (2.0 mL, 2.0 mmol) was added slowly toCompound 41 (223 mg, 0.50 mmol) in DCM (2 mL). The solution was stirredat RT for 75 min then slowly quenched with 1.1 mL of 7 M NH₃ in MeOH (8mmol). The resulting salts were filtered off and the filtrate purifiedby MPLC (SiO₂, 0-15% (10% NH₄OH/MeOH)/DCM) followed by reverse-phaseprep HPLC (C18, 0-40% 0.1% TFA in ACN/0.1% TFA in water) to giveCompound 42 as its TFA salt. ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.40 (br.s., 1H), 8.97 (br. s., 1H), 7.33 (d, J=9.0 Hz, 1H), 7.00 (d, J=8.4 Hz,1H), 6.74 (d, J=2.2 Hz, 1H), 6.64 (dd, J=8.4, 2.4 Hz, 1H), 4.43 (ddd,J=12.7, 8.9, 6.6 Hz, 1H), 3.94 (d, J=5.9 Hz, 1H), 3.42-3.35 (m, 1H),3.31 (d, J=19.6 Hz, 1H), 3.13-3.04 (m, 2H), 3.03-2.80 (m, 6H), 2.56 (t,J=5.1 Hz, 1H), 2.47-2.28 (m, 2H), 2.24 (dd, J=13.3, 6.3 Hz, 1H), 1.78(t, J=13.0 Hz, 1H), 1.33 (d, J=12.5 Hz, 1H), 1.18 (t, J=7.4 Hz, 3H),1.12-1.00 (m, 1H), 0.74-0.65 (m, 1H), 0.65-0.56 (m, 1H), 0.53-0.46 (m,1H), 0.45-0.36 (m, 1H). LC/MS, m/z=435 [M+H]⁺ (Calc: 434).

In a similar manner, the following compounds were prepared:

N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)benzenesulfonamide(TFA salt) (Compound 43) was prepared: ¹H NMR δ_(H) (400 MHz, DMSO-d₆):9.37 (br. s., 1H), 8.93 (br. s., 1H), 7.96 (d, J=8.6 Hz, 1H), 7.78-7.71(m, 2H), 7.63-7.50 (m, 3H), 6.98 (d, J=8.4 Hz, 1H), 6.70-6.60 (m, 3H),4.49-4.39 (m, 1H), 3.91 (d, J=5.9 Hz, 1H), 3.39-3.25 (m, 2H), 3.10-2.93(m, 3H), 2.89-2.78 (m, 2H), 2.45-2.25 (m, 2H), 2.20 (dd, J=13.3, 6.5 Hz,1H), 1.75 (t, J=12.9 Hz, 1H), 1.30 (d, J=12.5 Hz, 1H), 1.10-1.00 (m,1H), 0.72-0.64 (m, 1H), 0.64-0.56 (m, 1H), 0.51-0.43 (m, 1H), 0.43-0.34(m, 1H). LC/MS, m/z=483 [M+H]⁺ (Calc: 482); and

N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)methanesulfonamide(TFA salt) (Compound 108): ¹H NMR (DMSO-d₆) δ: 9.39 (s, 1H), 8.97 (br.s., 1H), 7.37 (d, J-9.0 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.74 (d, J=2.2Hz, 1H), 6.64 (dd, J=8.3, 2.3 Hz, 1H), 6.62 (s, 1H), 4.52-4.40 (m, 1H),3.94 (d, J=5.9 Hz, 1H), 3.31 (d, J=19.8 Hz, 1H), 3.15-2.90 (m, 4H), 2.88(s, 3H), 2.85-2.80 (m, 1H), 2.45-2.31 (m, 2H), 2.26 (dd, J=13.4, 6.6 Hz,1H), 1.75 (t, J=13.0 Hz, 1H), 1.34 (d, J=12.1 Hz, 1H), 1.12-1.01 (m,1H), 0.73-0.64 (m, 1H), 0.64-0.56 (m, 1H), 0.56-0.44 (m, 1H), 0.44-0.36(m, 1H). LC/MS, m/z=421 [M+H]⁺ (Calc: 420).

Example 15 Synthesis of(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-7-(2-hydroxyethyl)-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(Compound 46)

To a solution of Compound 1 (1.3 g, 3.04 mmol) in 30 mL of toluene wasadded PTSA.H₂O (0.636 g, 3.34 mmol) followed by ethylene glycol (0.5 mL,9.12 mmol) dropwise via syringe. The resulting mixture was heated atreflux with a Dean-Stark trap. After 24 h, LC/MS analysis revealed a 4:1mixture of product to starting material. An additional 0.5 mL ofethylene glycol (0.912 mmol) was added to the reaction and the mixturewas heated at reflux for 3 days. The mixture was cooled to 0° C. thenquenched with solid NaHCO₃. Satd. aq. NaHCO₃ was added and the organiclayer was separated.

The aqueous layer was extracted with Et₂O (3×) and the combined organicswere washed with brine. The organic layer was dried over Na₂SO₄,filtered, and concentrated to give crude Compound 44 as an oil that wasused in the next step without further purification. LC/MS, m/z=472.4[M+H]⁺ (Calc: 471.6).

To a −78° C. solution of Compound 44 (0.788 g, 1.67 mmol) in 17 mL ofanhydrous DCM was added a 1.0 M solution of DIBAL in hexanes (8.4 mL,8.4 mmol) dropwise via syringe. The reaction was allowed to warm slowlyto −30° C. over 2 h. LC/MS showed that the reaction was complete. MeOH(0.35 mL) was added dropwise and the reaction mixture warmed to RT. Themixture was diluted with satd. aq. Rochelle's salt and DCM and stirredvigorously for 1 h. The layers were separated. The aqueous layer wasextracted with DCM (2×). The combined organics were washed with brine,dried over Na₂SO₄, filtered, and concentrated. Crude Compound 45 (0.670g, 93%) was used in the next step without further purification. LC/MS,m/z=430.2 [M+H]⁺ (Calc: 429.6).

To Compound 45 (0.137 g, 0.319 mmol) was added 1.6 mL of 1 N aq. HCl.The resulting solution was maintained at RT for 60 h. The reactionmixture was cooled to 0° C. and basified with conc. NH₄OH. The mixturewas diluted with EtOAc, the layers were separated and the aqueous layerwas extracted with EtOAc (2×). The combined organics were washed withbrine, dried over Na₂SO₄, filtered, and concentrated. Purification byreverse-phase prep HPLC (C18, 0-60% 0.1% TFA in ACN/0.1% TFA in water)with subsequent neutralization with ammonium carbonate resin andlyophilization gave 31 mg (25%) of Compound 46 as a fluffy, white solid(as the TFA salt). ¹H NMR δ_(H) (400 MHz, CD₃OD): 7.00 (d, J=8.3 Hz,1H), 6.83 (s, 1H), 6.71 (d, J=8.3 Hz, 1H), 3.78 (s, 3H), 3.67-3.53 (m,2H), 3.41-3.18 (m, 1H), 3.14 (d, J=13.6 Hz, 1H), 3.08 (d, J=18.3 Hz,2H), 2.87 (d, J=13.6 Hz, 2H), 2.74-2.60 (m, 1H), 2.59-2.39 (m, 2H),2.34-2.21 (m, 1H), 2.20-2.09 (m, 1H), 2.07-1.83 (m, 2H), 1.60 (t, J=12.9Hz, 1H), 1.32-1.11 (m, 2H), 1.03-0.83 (m, 1H), 0.71-0.50 (m, 2H),0.34-0.10 (m, 2H). LC/MS, m/z=386.3 [M+H](Calc: 385.50).

Example 16 Synthesis of(4bR,7S,8aS,9R)-7-(2-(benzyloxy)ethyl)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(Compound 48)

To a suspension of NaH (0.028 g, 1.19 mmol) in 3 mL of anhydrous DMFcooled to 0° C. was added Compound 45 (0.170 g, 0.396 mmol) in 1 mL ofanhydrous DMF dropwise via syringe. The suspension was maintained for0.5 h whereupon benzyl bromide (0.052 mL, 0.435 mmol) was addeddropwise. The reaction was maintained for 24 h at RT. LC/MS analysisshowed that the reaction was not complete. An additional 10 mg (˜1equiv) of NaH was added and the reaction was maintained for another 24h. LC/MS now showed that the reaction was mostly complete. The reactionwas slowly quenched with H₂O then diluted with EtOAc. The layers wereseparated and the aqueous layer was further extracted with EtOAc (2×).The combined organics were washed with brine, dried over Na₂SO₄,filtered, and concentrated. Crude Compound 47 (176 mg) was used in thenext step without further purification. LC/MS, m/z=520.4 [M+H]⁺ (Calc:519.7).

To Compound 47 (0.176 g, 0.339 mmol) in 1.0 mL of THF was added 1.7 mLof 1 N aq. HCl. The resulting light orange solution was maintained for60 h at RT. LC/MS analysis showed the reaction was complete. Thereaction mixture was cooled to 0° C. and basified with conc. NH₄OH. Themixture was diluted with EtOAc, the layers separated and the aqueouslayer was extracted with EtOAc (2×). The combined organics were washedwith brine, dried over Na₂SO₄, filtered, and concentrated. Purificationby reverse-phase prep HPLC (C18, 20-90% 0.1% TFA in ACN/0.1% TFA inwater) with subsequent neutralization with ammonium carbonate resin andlyophilization gave 31 mg (19%) of the Compound 48 as a fluffy, whitesolid. ¹H NMR δ_(H) (400 MHz, CD₃OD): 7.40-7.18 (m, 5H), 7.02 (d, J=8.4Hz, 1H), 6.80 (s, 1H), 6.72 (d, J=8.1 Hz, 1H), 4.41 (s, 2H), 3.75 (s,3H), 3.41 (t, J=6.4 Hz, 2H), 3.27-2.95 (m, 4H), 2.87-2.58 (m, 3H),2.57-2.34 (m, 2H), 2.34-2.01 (m, 2H), 2.01-1.86 (m, 2H), 1.57 (t, J=13.1Hz, 1H), 1.31-1.09 (m, 2H), 1.04-0.83 (m, 1H), 0.71-0.47 (m, 2H),0.33-0.09 (m, 214). LC/MS, m/z=476.3 [M+H]⁺ (Calc: 475.6).

In a similar manner, the following compounds were prepared:

(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-7-(2-methoxyethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(Compound 49): ¹H NMR δ_(H) (400 MHz, CD₃OD): 7.04 (d, J=8.4 Hz, 1H),6.81 (d, J-2.2 Hz, 1H), 6.72 (dd, J=8.4, 2.0 Hz, 1H), 3.75 (s, 3H),3.37-3.33 (m, 3H), 3.24 (s, 3H), 3.18-2.92 (m, 3H), 2.89-2.75 (m, 2H),2.74-2.61 (m, 1H), 2.59-2.37 (m, 2H), 2.32-2.03 (m, 2H), 1.90-1.80 (m,2H), 1.67-1.47 (m, 1H), 1.24-1.06 (m, 2H), 1.02-0.82 (m, TH), 0.68-0.46(m, 2H), 0.34-0.11 (m, 2H). LC/MS, m/z=400.2 [M+H]⁺ (Calc: 399.5); and

(4bR,7S,8aS,9R)-7-(2-(benzyloxy)ethyl)-8a-hydroxy-3-methoxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(Compound 50): ¹H NMR δ_(H) (400 MHz, CD₃OD): 7.41-7.21 (m, 5H), 7.14(d, J=8.4 Hz, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.84 (dd, J=8.5, 2.5 Hz, 1H),4.39 (s, 2H), 3.78 (s, 3H), 3.57 (d, J=6.4 Hz, 1H), 3.48-3.35 (m, 3H),3.27-3.16 (m, 1H), 3.15-3.06 (m, 2H), 3.05-2.94 (m, 2H), 2.92 (s, 3H),2.74-2.62 (m, 1H), 2.58-2.44 (m, 1H), 2.07 (dd, J=13.9, 6.4 Hz, 1H),2.00-1.86 (m, 1H), 1.75-1.63 (m, 1H), 1.50-1.38 (m, 1H), 1.35-1.22 (m,1H). LC/MS, m/z=436.2 [M+H]⁺ (Calc: 435.6).

Example 17 Synthesis of(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-hydroxyethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(Compound 54)

To a 0° C. solution of Compound 1 (1.4 g, 3.27 mmol) in 33 mL ofanhydrous DCM was added 13.1 mL (13.1 mmol) of a 1.0 M solution of BBr₃in DCM dropwise via syringe. The resulting yellow suspension wasmaintained at 0° C. for 15 min. LC/MS analysis showed that the reactionwas complete. The reaction was quenched with 10 mL of EtOH then dilutedwith DCM and saturated aqueous NaHCO₃. The layers were separated and theaqueous layer was extracted with DCM (2×). The combined organics werewashed with brine, dried over Na₂SO₄, filtered, and concentrated toafford 1.08 g (80%) of Compound 51. LC/MS, m/z=414.2 [M+H]⁺ (Calc:413.5).

To a solution of Compound 51 (0.260 g, 0.629 mmol) in 6.3 mL of benzenewas added ethlyene glycol (0.140 mL, 2.52 mmol) followed by PTSA (0.132g, 0.692 mmol). The reaction was heated at reflux with a Dean-Stark trapfor 1 h. LC/MS analysis showed that the reaction was complete. Themixture was quenched with solid NaHCO₃ at 0° C. Satd. aq. NaHCO₃ wasadded and the organic layer was separated. The aqueous layer wasextracted with EtOAc (3×) and the combined organics were washed withbrine. The organic layer was dried over Na₂SO₄, filtered, andconcentrated. Purification by flash chromatography (SiO₂, 0-5% MeOH/DCM)gave 108 mg (38%) of Compound 52. LC/MS, m/z=458.2 [M+H]⁺ (Calc: 457.6).

To a −78° C. solution of Compound 52 (0.108 g, 0.236 mmol) in 2.4 mL ofanhydrous DCM was added a 1.0 M solution of DIBAL in hexanes (1.18 mL,1.18 mmol) dropwise via syringe. The reaction was allowed to warm slowlyto −30° C. over 2 h. LC/MS showed that the reaction was complete. MeOH(0.5 mL) was added dropwise and the reaction mixture warmed to RT. Themixture was diluted with satd. aq. Rochelle's salt and DCM and stirredvigorously for 1 h. The layers were separated and the aqueous layer wasextracted with DCM (2×). The combined organics were washed with brine,dried over Na₂SO₄, filtered, and concentrated. The crude Compound 53(0.097 g, 99%) was used in the next step without further purification.LC/MS, m/z:=416.4 [M+H]⁺ (Calc: 415.5).

To Compound 53 (0.097 g, 0.233 mmol) was added 1.2 mL of 1 N aq. HCl.The resulting solution was maintained at RT for 18 h. LC/MS showed thereaction was complete. The reaction mixture was cooled to 0° C. andbasified with conc. NH₄OH. The reaction was diluted with EtOAc and H₂O,the layers separated and the aqueous layer was extracted with EtOAc(2×). The combined organics were washed with brine, dried over Na₂SO₄,filtered, and concentrated. Purification by reverse-phase prep HPLC(C18, 0-40% 0.1% TFA in ACN/0.1% TFA in water) with subsequentneutralization with ammonium carbonate resin and lyophilization afforded37 mg (43%) of Compound 54 as a fluffy, white solid. ¹H NMR δ_(H) (400MHz, CD₃OD): 6.94 (d, J=8.4 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.59 (dd,J=8.3, 2.3 Hz, 1H), 3.65-3.42 (m, 2H), 3.08 (d, J=13.2 Hz, 3H),3.04-2.93 (m, 1H), 2.79 (d, J=13.6 Hz, 2H), 2.72-2.60 (m, 1H), 2.58-2.36(m, 2H), 2.31-2.05 (m, 2H), 1.99-1.79 (m, 2H), 1.67-1.51 (m, 1H),1.29-1.03 (m, 2H), 0.99-0.84 (m, 1H), 0.68-0.49 (m, 2H), 0.27-0.13 (m,2H). LC/MS, m/z=372.2 [M+H]⁺ (Calc: 371.5).

Example 18 Synthesis of(4bR,7S,8aS,9R)-3-(benzyloxy)-11-(cyclopropylmethyl)-8a-hydroxy-7-(2-hydroxyethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(Compound 58)

To a solution of Compound 52 (0.457 g, 1.00 mmol) in 4 mL of anhydrousDMF was added imidazole (170 mg, 2.50 mmol) followed by TBDPSCl (0.462mL, 1.80 mmol) via syringe. The reaction was maintained for 5 days atRT. LC/MS analysis showed that the reaction was mostly complete. Satd.aq. NaHCO₃ and EtOAc were added, the layers separated and the aqueouslayer was extracted with EtOAc (2×). The combined organics were washedwith brine, dried over Na₂SO₄, filtered, and concentrated. Purificationby flash chromatography (SiO₂, 0-5% MeOH/DCM) gave 0.610 g (88%) ofCompound 55. LC/MS, m/z=696.4 [M+H]⁺ (Calc: 695.9).

To a −78° C. solution of Compound 55 (0.310 g, 0.445 mmol) in 4 mL ofanhydrous DCM was added a 1.0 M solution of DIBAL in hexanes (2.23 mL,2.23 mmol) dropwise via syringe. The reaction was allowed to warm slowlyto −30° C. over 2 h. LC/MS showed that the reaction was complete. MeOH(0.3 mL) was added dropwise and the reaction mixture warmed to RT. Themixture was diluted with satd. aq. Rochelle's salt and DCM and stirredvigorously for 1 h. The layers were separated. The aqueous layer wasextracted with DCM (2×). The combined organics were washed with brine,dried over Na₂SO₄, filtered, and concentrated. Purification by flashchromatography (SiO₂, 0-10% MeOH/DCM) gave 0.265 g (91%) of Compound 56.LC/MS, m/z=654.4 [M+I]⁺ (Calc: 653.9).

To a 0° C. suspension of NaH (0.039 g, 1.62 mmol) in 3 mL of anhydrousDMF was added Compound 56 (0.265 g, 0.405 mmol) in 1 mL of anhydrous DMFdropwise via syringe. The suspension was maintained at 0° C. for 0.5 hwhereupon benzyl bromide (0.058 mL, 0.486 mmol) was added dropwise. Thereaction was maintained for 4 h at RT. The reaction was slowly quenchedwith H₂O and diluted with EtOAc. The layers were separated and theaqueous layer was extracted with EtOAc (2×). The combined organics werewashed with brine, dried over Na₂SO₄, filtered, and concentrated.Purification by flash chromatography (SiO₂, 0-5% MeOH/DCM) gave 29 mg ofCompound 57 as a clear colorless residue. LC/MS, m/z=506.3 [M+H]⁺ (Calc:505.7).

To Compound 57 (0.029 g, 0.057 mmol) in 0.5 mL of THF was added 1.2 mLof 1 N aq. HCl. The resulting solution was maintained at RT for 18 h.LC-MS showed the reaction was complete. The reaction mixture was cooledto 0° C. and basified with conc.

NH₄OH. The mixture was diluted with EtOAc, the layers were separated andthe aqueous layer was extracted with EtOAc (2×). The combined organicswere washed with brine, dried over Na₂SO₄, filtered, and concentrated.Purification by reverse-phase prep HPLC (C18, 0-60% 0.1% TFA in ACN/0.1%TFA in water) with subsequent neutralization with ammonium carbonateresin and lyophilization afforded 11 mg (42%) of Compound 58 as afluffy, white solid. ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 7.53-7.27 (m, 5H),7.03 (d, J=8.4 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 6.79 (dd, J=8.4, 2.6 Hz,1H), 5.06-4.92 (m, 2H), 4.81 (s, 1H), 4.30 (t, J=5.2 Hz, 1H), 3.09 (d,J=5.9 Hz, 1H), 3.06-2.84 (m, 3H), 2.80-2.63 (m, 2H), 2.58-2.52 (m, 1H),2.43-2.22 (m, 3H), 2.16-2.03 (m, 1H), 1.97-1.79 (m, 2H), 1.79-1.66 (m,1H), 1.43-1.28 (m, 1H), 1.06 (d, J=12.1 Hz, 1H), 0.99-0.77 (m, 3H),0.37-0.59 (m, 2H), 0.01-0.21 (m, 2H). LC/MS, m/z=462.3 [M+H]⁺ (Calc:461.6).

Example 19

In a manner similar to that described in EXAMPLES 1-3, the followingcompounds were prepared:

ethyl2-((4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetate(TFA salt) (Compound 59): ¹H NMR δ_(H) (400 MHz, CD₃OD): 7.16 (d, J=8.4Hz, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.85 (dd, J=8.5, 2.5 Hz, 1H), 3.97-4.13(m, 2H), 3.78 (s, 3H), 3.60 (d, J=6.4 Hz, 1H), 3.33-3.47 (m, 2H),3.19-3.28 (m, 1H), 3.17 (d, J=13.9 Hz, 1H), 3.10 (dd, J=12.5, 4.4 Hz,1H), 2.99 (d, J=13.9 Hz, 1H), 2.93 (s, 3H), 2.62-2.75 (m, 1H), 2.50-2.62(m, 1H), 2.45 (dd, J=16.8, 7.8 Hz, 1H), 2.00-2.14 (m, 2H), 1.70-1.86 (m,1H), 1.38-1.49 (m, 1H), 1.18 (t, J=7.2 Hz, 3H). LC/MS, m/z=388.2 [M+H]⁺(Calc: 387.5);

2-((4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)aceticacid (TFA salt) (Compound 60): ¹H NMR δ_(H) (400 MHz, CD₃OD): 7.16 (d,J=8.6 Hz, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.85 (dd, J=8.5, 2.5 Hz, 1H),3.78 (s, 3H), 3.60 (d, J=6.4 Hz, 1H), 3.38 (s, 1H), 3.33-3.37 (m, 1H),3.20-3.28 (m, 1H), 3.18 (d, J=13.9 Hz, 1H), 3.10 (dd, J=12.7, 4.3 Hz,1H), 2.99 (d, J=13.9 Hz, 1H), 2.93 (s, 3H), 2.62-2.79 (m, 1H), 2.45-2.60(m, 2H), 2.09 (dd, J=13.9, 6.2 Hz, 1H), 1.98 (dd, J=16.9, 5.7 Hz, 1H),1.66-1.79 (m, 1H), 1.37-1.52 (m, 1H). LC/MS, m/z=360.2 [M+H]⁺ (Calc:359.4); and

2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)aceticacid (Compound 61): ¹H NMR δ_(H) (400 MHz, CD₃OD): 7.06 (d, J=8.4 Hz,1H), 6.78 (d, J=2.2 Hz, 1H), 6.70 (dd, J=8.4, 2.4 Hz, 1H), 3.58 (d,J=6.2 Hz, 1H), 3.35 (s, 3H), 3.03-3.27 (m, 3H), 2.86-3.00 (m, 4H),2.63-2.77 (m, 1H), 2.44-2.61 (m, 2H), 2.09 (dd, J=13.6, 6.2 Hz, 1H),1.98 (dd, J=16.9, 5.7 Hz, 1H), 1.66-1.83 (m, 1H), 1.34-1.47 (m, 1H).LC/MS, m/z=346.2 [M+H]⁺ (Calc: 345.4).

Example 20 Synthesis of(4bR,8aS,9R,E)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-7-(3-methylbutylidene)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 62) and(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-isopentyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 64)

Isovaleraldehyde (0.57 mL, 5.3 mmol) was added to Compound 7 (1 g, 2.5mmol) and 2.5 M aq. NaOH (3.2 mmol, 7.9 mmol) in MeOH (6 mL). Thesolution was stirred at RT for 45 h, and an additional aliquot ofisovaleraldehyde (0.57 mL, 5.3 mmol) was added. After 3 days EtOAc wasadded, the resulting mixture was washed with sat. NaHCO₃, dried withNa₂SO₄, and concentrated. The crude material was purified by MPLC (SiO₂,0-30% acetone/hexanes) followed by purification by prep-HPLC (C18, 0-60%0.1% TFA in ACN/0.1% TFA in water) to give Compound 62 as its TFA salt.¹H NMR δ_(H) (400 MHz, DMSO-d₆): 8.76 (br. s., 1H), 6.89 (d, J=8.4 Hz,1H), 6.61 (dd, J=8.4, 2.4 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 6.25 (t,J=7.0 Hz, 1H), 6.07 (br. s., 1H), 3.79 (d, J=5.9 Hz, 1H), 3.46 (s, 3H),3.02-3.21 (m, 3H), 2.87 (d, J=16.9 Hz, 1H), 2.53-2.80 (m, 4H), 2.11 (d,J=17.4 Hz, 1H), 2.03 (td, J=13.8, 4.8 Hz, 1H), 1.64-1.75 (m, 1H),1.54-1.63 (m, 1H), 1.35-1.47 (m, 1H), 1.15 (d, J=12.1 Hz, 1H), 0.77-0.88(m, 1H), 0.62-0.71 (m, 1H), 0.60 (d, J=6.6 Hz, 3H), 0.53 (d, J=6.6 Hz,3H), 0.44-0.51 (m, 1H), 0.35-0.43 (m, 1H), 0.14-0.28 (m, 2H). LC/MS,m/z=410 [M+H]⁺ (Calc: 409).

To a crude solution of Compound 62 (600 mg, 1.5 mmol) in MeOH (30 mL)was carefully added 90 mg of 10% Pd/C. The solution was evacuated andfilled with 1 atm of H₂ three times, after which it was stirred under 1atm of H₂ at RT for 66 h. Filtration through Celite followed byconcentration yielded 600 mg of Compound 63 as a clear oil which wasused in subsequent steps without purification. LC/MS, m/z=412 [M+H]⁺(Calc: 4H).

A 1M solution of BBr₃ in DCM (5.8 mL, 5.8 mmol) was added slowly toCompound 63 (600 mmol, 1.5 mmol) in DCM (2 mL). The solution was stirredat RT for 75 min. then slowly quenched with 3.3 mL of 7M NH₃ in MeOH(23.1 mmol). The resulting salts were filtered off and the filtratepurified by MPLC (SiO₂, 0-20% (10% NH₄OH/MeOH)/DCM) followed byprep-HPLC (C18, 0-60% 0.1% TFA in ACN/0.1% TFA in water) to giveCompound 64 as its TFA salt. ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.29 (s,1H), 8.87 (br s., 1H), 6.91 (d, J=8.4 Hz, 1H), 6.63 (d, J=2.2 Hz, 1H),6.57 (dd, J=8.4, 2.4 Hz, 1H), 6.28 (s, 1H), 3.82 (d, J=5.7 Hz, 1H),3.33-3.26 (m, 1H), 3.22 (d, J=19.6 Hz, 1H), 3.04 (dd, J=23.5, 12.1 Hz,1H), 2.90 (d, J=13.6 Hz, 2H), 2.85-2.74 (m, 1H), 2.67 (d, J=13.6 Hz,1H), 2.65-2.59 (m, 1H), 2.40-2.21 (m, 2H), 2.05 (dd, J=13.6, 6.2 Hz,1H), 1.59-1.47 (m, 1H), 1.42-1.30 (m, 2H), 1.21 (d, J=12.5 Hz, 1H),1.06-0.88 (m, 3H), 0.81-0.70 (m, 7H), 0.67-0.59 (m, 1H), 0.59-0.51 (m,1H), 0.45-0.31 (m, 2H). LC/MS, m/z=398 [M+H]⁺ (Calc: 397).

In a similar manner, the following compounds were prepared:

(4bR,7S,8aS,9R)-7-(cyclopentylmethyl)-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 65): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.29 (br. s.,1H), 8.86 (br. s., 1H), 6.90 (d, J=8.1 Hz, 1H), 6.62 (d, J=2.2 Hz, 1H),6.57 (dd, J=8.4, 2.4 Hz, 1H), 6.30 (s, 1H), 3.83 (d, J=5.9 Hz, 1H),3.33-3.17 (m, 2H), 3.04 (dd, J=19.8, 6.2 Hz, 1H), 2.96-2.87 (m, 2H),2.85-2.76 (m, 1H), 2.67 (d, J=13.6 Hz, 2H), 2.39-2.20 (m, 2H), 2.08 (dd,J=13.6, 6.2 Hz, 1H), 1.72-1.25 (m, 9H), 1.21 (d, J=12.5 Hz, 1H),1.05-0.74 (m, 4H), 0.67-0.59 (m, 1H), 0.59-0.50 (m, 1H), 0.46-0.38 (m,1H), 0.38-0.29 (m, 1H). LC/MS, m/z=410 [M+H]⁺ (Calc: 409);

(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-methylbutyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 66): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 8.98-8.87 (m,1H), 6.98 (d, J=8.4 Hz, 1H), 6.69 (d, J=2.2 Hz, 1H), 6.64 (dd, J=8.3,2.3 Hz, 1H), 6.38 (br. s., 1H), 3.90 (t, J=5.7 Hz, 1H), 3.32-3.07 (m,3H), 3.04-2.92 (m, 2H), 2.91-2.70 (m, 3H), 2.46-2.27 (m, 2H), 2.08 (td,J=14.0, 6.4 Hz, 1H), 1.59 (dt, J=13.6, 6.6 Hz, 1H), 1.48-1.38 (m, 1H),1.38-1.14 (m, 4H), 1.06 (d, J=7.3 Hz, 2H), 0.84-0.73 (m, 7H), 0.72-0.66(m, 1H), 0.66-0.54 (m, 2H), 0.54-0.45 (m, 1H), 0.45-0.37 (m, 1H). LC/MS,m/z=398 [M+H]⁺ (Calc: 397);

(4bR,7S,8aS,9R)-7-butyl-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 67): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.36 (s, 1H),8.93 (br. s., 1H), 6.98 (d, J=8.1 Hz, 1H), 6.69 (d, J=2.0 Hz, 1H), 6.64(dd, J=8.1, 2.2 Hz, 1H), 6.34 (s, 2H), 3.89 (d, J=5.5 Hz, 1H), 3.33-3.20(m, 2H), 3.11 (dd, J=18.5, 5.9 Hz, 1H), 2.98 (d, J=13.6 Hz, 2H),2.91-2.82 (m, 1H), 2.78-2.69 (m, 2H), 2.45-2.28 (m, 2H), 2.11 (dd,J=13.8, 6.1 Hz, 1H), 1.57 (td, J=13.3, 7.4 Hz, 1H), 1.42 (t, J=13.3 Hz,1H), 1.33-1.01 (m, 7H), 0.90-0.84 (m, 1H), 0.81 (t, J=7.0 Hz, 3H),0.74-0.65 (m, 1H), 0.65-0.57 (m, 1H), 0.54-0.45 (m, 1H), 0.44-0.36 (m,1H). LC/MS, m/z=384 [M+H]⁺ (Calc: 383);

(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-neopentyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 68) ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.37 (br. s.,1H), 8.92 (br. s., 1H), 6.98 (d, J=8.1 Hz, 1H), 6.70 (d, J=2.0 Hz, 1H),6.64 (dd, J=8.1, 2.2 Hz, 1H), 6.43 (s, 1H), 3.90 (d, J=5.7 Hz, 1H),3.40-3.32 (m, 1H), 3.29 (d, J=19.6 Hz, 1H), 3.14-2.96 (m, 3H), 2.93-2.85(m, 1H), 2.81-2.72 (m, 2H), 2.47-2.30 (m, 2H), 2.09 (dd, J=13.6, 6.4 Hz,1H), 1.95 (dd, J=14.0, 4.7 Hz, 1H), 1.52 (t, J=13.3 Hz, 1H), 1.28 (d,J=11.9 Hz, 1H), 1.12-1.00 (m, 1H), 0.80 (s, 9H), 0.74-0.58 (m, 2H),0.54-0.37 (m, 3H). LC/MS, m/z=398 [M+H]⁺ (Calc: 397);

(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-isobutyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 69) ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.29 (s, 1H),8.85 (br. s., 1H), 6.91 (d, J=8.4 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 6.57(dd, J=8.3, 2.3 Hz, 1H), 6.31 (s, 1H), 3.83 (d, J=5.9 Hz, 1H), 3.33-3.25(m, 1H), 3.22 (d, J=19.6 Hz, 1H), 3.04 (dd, J=22.0, 8.1 Hz, 1H),2.96-2.87 (m, 2H), 2.85-2.76 (m, 1H), 2.75-2.65 (m, 2H), 2.39-2.21 (m,2H), 2.02 (dd, J-13.8, 6.3 Hz, 1H), 1.48-1.28 (m, 3H), 1.21 (d, J=12.8Hz, 1H), 1.06-0.94 (m, 1H), 0.73 (d, J=2.6 Hz, 3H), 0.72 (d, J=2.9 Hz,3H), 0.68-0.58 (m, 2H), 0.59-0.51 (m, 1H), 0.47-0.38 (m, 1H), 0.38-0.30(m, 1H). LC/MS, m/z=384 [M+H]⁺ (Calc: 383);

(4bR,7S,8aS,9R)-7-(cyclohexylmethyl)-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 70): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.29 (br. s.,1H), 8.86 (br. s., 1H), 6.90 (d, J=8.4 Hz, 1H), 6.62 (d, J=2.2 Hz, 1H),6.57 (dd, J=8.3, 2.3 Hz, 1H), 6.30 (s, 1H), 3.84 (d, J:=0.5.9 Hz, 1H),3.32-3.17 (m, 2H), 3.05 (dd, J=22.2, 7.9 Hz, 1H), 2.97-2.86 (m, 2H),2.84-2.70 (m, 2H), 2.67 (d, J=13.9 Hz, 1H), 2.40-2.20 (m, 2H), 2.03 (dd,J=13.6, 6.2 Hz, 1H), 1.70-1.37 (m, 6H), 1.31 (t, J=13.2 Hz, 1H), 1.21(d, J-12.5 Hz, 1H), 1.14-0.94 (m, 5H), 0.79-0.68 (m, 1H), 0.68-0.51 (m,4H), 0.47-0.38 (m, 1H), 0.38-0.29 (m, 1H). LC/MS, m/z=424 [M+H]⁺ (Calc:423);

(4bR,7S,8aS,9R)-7-benzyl-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 71) ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.33 (br. s.,1H), 8.80 (br. s., 1H), 7.20-7.13 (m, 2H), 7.13-7.03 (m, 3H), 6.92 (d,J=8.4 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.59 (dd, J=8.3, 2.3 Hz, 1H),6.20 (s, 1H), 3.76 (d, J=5.9 Hz, 1H), 3.30-3.16 (m, 2H), 3.05-2.94 (m,4H), 2.88 (d, J=10.8 Hz, 1H), 2.81-2.70 (m, 2H), 2.39-2.20 (m, 2H), 1.98(dd, J=14.7, 10.1 Hz, 1H), 1.84 (dd, J=13.6, 5.7 Hz, 1H), 1.42 (t,J=13.1 Hz, 1H), 1.22 (d, J=12.3 Hz, 1H), 1.01-0.90 (m, 1H), 0.63-0.54(m, 1H), 0.54-0.44 (m, 1H), 0.42-0.34 (m, 1H), 0.34-0.25 (m, 1H). LC/MS,m/z=418 [M+H]⁺ (Calc: 417);

(4bS,7S,8aR,9R)-11-(cyclopropylmethyl)-7-isopropyl-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 72): ¹H NMR δ_(H) (400 MHz, CD₃OD): 7.05 (d, J=8.6Hz, 1H), 6.80 (s, 1H), 6.69-6.76 (m, 1H), 4.05 (br. s., 1H), 3.67 (s,3H), 3.30 (d, J=12.7 Hz, 1H), 2.95-3.12 (m, 3H), 2.48-2.61 (m, 3H),2.28-2.39 (m, 1H), 1.81-2.10 (m, 3H), 1.67 (d, J=14.3 Hz, 1H), 1.00-1.25(m, 2H), 0.76 (d, J=6.8 Hz, 3H), 0.69 (d, J=7.0 Hz, 2H), 0.64-0.72 (m,2H), 0.34-0.53 (m, 5H). LC/MS, m/z=368.3 [M+H]⁺ (Calc: 367.5);

(4bS,7S,8aR,9R)-11-(cyclopropylmethyl)-3-hydroxy-7-isopropyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 73): ¹H NMR δ_(H) (400 MHz, CD₃OD): 6.95 (d, J=8.1Hz, 1H), 6.66-6.71 (m, 1H), 6.54-6.62 (m, 1H), 4.03 (br. s., 1H),3.24-3.34 (m, 1H), 3.11-3.18 (m, 1H), 2.95-3.08 (m, 4H), 2.45-2.61 (m,3H), 2.26-2.37 (m, 1H), 1.88-2.08 (m, 3H), 1.63 (d, J=13.8 Hz, 1H),1.14-1.29 (m, 1H), 1.00-1.11 (m, 1H), 0.64-0.80 (m, 5H), 0.52 (d, J=6.8Hz, 3H), 0.35-0.44 (m, 2H). LC/MS, m/z=354.1 [M+H]⁺ (Calc: 353.5); and

(4bS,7R,8aR,9R)-11-(cyclopropylmethyl)-3-hydroxy-7-isopropyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 74): ¹H NMR δ_(H) (400 MHz, CD₃OD): 6.98 (d, J=8.3Hz, 1H), 6.61 (d, J=8.3 Hz, 1H), 6.54 (s, 1H), 4.07 (br. s., 1H),3.25-3.29 (m, 1H), 3.15-3.22 (m, 3H), 2.74-2.89 (m, 2H), 2.50-2.70 (m,3H), 2.37-2.47 (m, 1H), 1.92-2.12 (m, 4H), 1.37 (d, J=14.7 Hz, 1H), 1.02(d, J=6.6 Hz, 1H), 0.89 (t, J=7.5 Hz, 6H), 0.59-0.74 (m, 2H), 0.29-0.43(m, 2H). LC/MS, m/z: 354.1 [M+H]⁺ (Calc: 353.5);

(4bS,7S,8aR,9R)-11-(cyclopropylmethyl)-3-hydroxy-7-isopentyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 104): ¹H NMR (DMSO-d₆) δ: 9.43 (br. s., 0.7H), 9.34(br. s., 0.3H), 9.31-9.21 (m, 1H), 6.95-6.85 (m, 1H), 6.64 (d, J=2.0 Hz,1H), 6.56 (dd, J=8.4, 2.4 Hz, 1H), 3.97 (br. s., 0.7H), 3.85 (br. s.,0.3H), 3.42-3.32 (m, 0.6H), 3.29-2.83 (m, 6H), 2.71-2.47 (m, 2H),2.41-2.24 (m, 1H), 2.17-2.06 (m, 0.5H), 2.02-1.81 (m, 2H), 1.55 (d,J=13.4 Hz, 1H), 1.51-1.41 (m, 1H), 1.41-1.28 (m, 1H), 1.10-0.83 (m, 5H),0.83-0.76 (m, 1H), 0.74 (d, J=6.8 Hz, 3H), 0.72 (d, J=6.8 Hz, 3H),0.65-0.53 (m, 2H), 0.40-0.25 (m, 2H). LC/MS, m/z=382.4 [M+H]⁺ (Calc:381.55);

(4bS,7S,8aR,9R)-7-(cyclopentylmethyl)-11-(cyclopropylmethyl)-3-hydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 105): ¹H NMR (DMSO-d₆) δ: 9.37 (br. s., 0.7H),9.31-9.23 (m, 1.3H), 6.94-6.86 (m, 1H), 6.64 (d, J=2.2 Hz, 1H), 6.56(dd, J=8.4, 2.4 Hz, 1H), 3.98 (br. s., 0.7H), 3.84 (br. s., 0.3H),3.43-3.33 (m, 0.7H), 3.33-2.82 (m, 7H), 2.76-2.58 (m, 1.7H), 2.56-2.46(m, 1H), 2.41-2.30 (m, 1H), 2.16-2.08 (m, 0.6H), 2.08-1.87 (m, 2H),1.73-1.30 (m, 10H), 1.10-0.74 (m, 6H), 0.68-0.53 (m, 2H), 0.41-0.26 (m,2H). LC/MS, m/z. 394.4 [M+H]⁺ (Calc: 393.56);

(4bR,7S,8aS,9R)-3,8a-dihydroxy-7-isopentyl-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 106): ¹H NMR (DMSO-d₆) δ: 9.37 (s, 1H), 9.24 (br.s., 1H), 6.99 (d, J=8.1 Hz, 1H), 6.69 (d, J=2.2 Hz, 1H), 6.64 (dd,J=8.4, 2.2 Hz, 1H), 6.26 (s, 1H), 3.54 (d, J=5.7 Hz, 1H), 3.29 (d,J=19.8 Hz, 1H), 3.08 (dd, J=19.8, 6.4 Hz, 1H), 3.00 (d, J=12.3 Hz, 1H),2.96 (d, J=13.9 Hz, 1H), 2.83 (d, J=4.8 Hz, 3H), 2.73 (d, J:=13.9 Hz,1H), 2.71-2.63 (m, 1H), 2.48-2.38 (m, 1H), 2.34-2.24 (m, 1H), 2.03 (dd,J=13.6, 6.2 Hz, 1H), 1.61-1.49 (m, 1H), 1.48-1.35 (m, 2H), 1.27 (d,J=12.5 Hz, 1H), 1.11-0.92 (m, 2H), 0.88-0.82 (m, 1H), 0.80 (d, J=6.8 Hz,3H), 0.78 (d, J=6.6 Hz, 3H). LC/MS, m/z=358.2 [M+H]⁺ (Calc: 357.49); and

(4bS,7S,8aR,9R)-7-(cyclopentylmethyl)-3-hydroxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 107): ¹H NMR (DMSO-d₆) δ: 9.37 (br. s., 1H), 9.24(br. s., 1H), 6.99 (d, J=8.4 Hz, 1H), 6.69 (d, J=2.2 Hz, 1H), 6.63 (dd,J=8.1, 2.2 Hz, 1H), 6.30 (s, 1H), 3.54 (d, J=5.9 Hz, 1H), 3.29 (d,J=19.8 Hz, 1H), 3.13-3.01 (m, 2H), 2.97 (d, J=13.9 Hz, 1H), 2.83 (d,J=4.8 Hz, 3H), 2.79-2.65 (m, 2H), 2.47-2.37 (m, 1H), 2.37-2.24 (m, 1H),2.06 (dd, J=13.6, 6.2 Hz, 1H), 1.78-1.32 (m, 9H), 1.27 (d, J=12.8 Hz,1H), 1.05-0.75 (m, 3H). LC/MS, m/z=370.4 [M+H]⁺ (Cal: 369.5).

Example 21

In a manner similar to that described in EXAMPLES 6 and 7, the followingcompounds were prepared:

(2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetyl)-L-alanine(TFA salt) (Compound 75): ¹H NMR δ_(H) (400 MHz, CD₃OD): 8.22 (d, J=6.8Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.78 (d, J=2.2 Hz, 1H), 6.69 (dd,J=8.3, 2.3 Hz, 1H), 4.39-4.25 (m, 1H), 3.57 (d, J=5.9 Hz, 1H), 3.43-3.33(m, 2H), 3.15 (d, J=14.1 Hz, 2H), 3.09 (dd, J=12.8, 4.2 Hz, 1H),2.97-2.88 (m, 4H), 2.77-2.63 (m, 1H), 2.62-2.45 (m, 2H), 2.11 (dd,J=13.8, 6.3 Hz, 1H), 1.88 (dd, J=15.2, 7.7 Hz, 1H), 1.77-1.64 (m, 1H),1.45-1.37 (m, 1H), 1.36 (d, J=7.5 Hz, 3H). LC/MS, m/z=417.2 [M+H]⁺(Calc: 416.47);

(4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-7-(2-oxo-2-(piperidin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 76): ¹H NMR δ_(H) (400 MHz, CD₃OD): 7.16 (d, J=8.4Hz, 1H), 6.91 (d, J=2.6 Hz, 1H), 6.84 (dd, J=8.5, 2.5 Hz, 1H), 3.77 (s,3H), 3.59 (d, J=6.2 Hz, 1H), 3.57-3.50 (m, 1H), 3.49-3.33 (m, 6H), 3.19(s, 2H), 3.10 (dd, J=12.7, 4.3 Hz, 1H), 2.98 (d, J=13.6 Hz, 1H),2.95-2.90 (m, 3H), 2.76 (dd, J=16.4, 6.9 Hz, 1H), 2.72-2.63 (m, 1H),2.62-2.50 (m, 1H), 2.09 (dd, J=13.6, 6.2 Hz, 1H), 1.90 (dd, J=16.5, 5.7Hz, 1H), 1.75-1.57 (m, 4H), 1.57-1.38 (m, 4H). LC/MS, m/z=427.2 [M+H]⁺(Calc: 426.6);

(4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-7-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 77): ¹H NMR δ_(H) (400 MHz, CD₃OD): 7.16 (d, J=8.6Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.84 (dd, J=8.4, 2.4 Hz, 1H), 3.77 (s,3H), 3.60 (d, J=6.2 Hz, 1H), 3.47 (d, J=6.8 Hz, 2H), 3.45-3.33 (m, 5H),3.27-3.16 (m, 2H), 3.10 (dd, J=12.5, 4.4 Hz, 1H), 2.98 (d, J=13.9 Hz,1H), 2.93 (s, 3H), 2.74-2.61 (m, 2H), 2.61-2.49 (m, 1H), 2.10 (dd,J=13.8, 6.1 Hz, 1H), 2.00-1.81 (m, 5H), 1.76-1.65 (m, 1H), 1.50-1.39 (m,1H). LC/MS, m/z=413.3 [M+H]⁺ (Calc: 412.5);

(4bR,7R,8aS,9R)-8a-hydroxy-7-(2-(4-hydroxypiperidin-1-yl)-2-oxoethyl)-3-methoxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 78): ¹H NMR δ_(H) (400 MHz, CD₃OD): 7.16 (d, J=8.4Hz, 1H), 6.93-6.88 (m, 1H), 6.84 (dd, J=8.5, 2.5 Hz, 1H), 4.11-3.91 (m,1H), 3.88-3.68 (m, 5H), 3.59 (d, J=6.2 Hz, 1H), 3.52-3.33 (m, 2H),3.28-3.01 (m, 5H), 2.98 (d, J=13.6 Hz, 1H), 2.93 (s, 3H), 2.82-2.73 (m,1H), 2.73-2.62 (m, 1H), 2.62-2.49 (m, 1H), 2.14-2.03 (m, 1H), 1.97-1.86(m, 1H), 1.86-1.75 (m, 2H), 1.75-1.66 (m, 1H), 1.58-1.31 (m, 3H). LC/MS,m/z=443.3 [M+H]⁺ (Calc: 442.6);

(4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-7-(2-morpholino-2-oxoethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 79): ¹H NMR δ_(H) (400 MHz, CD₃OD): 7.16 (d, J=8.6Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.84 (dd, J=8.5, 2.5 Hz, 1H), 3.77 (s,3H), 3.69-3.57 (m, 5H), 3.57-3.37 (m, 6H), 3.27-3.16 (m, 2H), 3.11 (dd,J=12.8, 4.2 Hz, 1H), 2.98 (d, J=13.6 Hz, 1H), 2.92 (s, 3H), 2.80-2.64(m, 2H), 2.61-2.51 (m, 1H), 2.09 (dd, J=13.8, 6.1 Hz, 1H), 1.91 (dd,J:=16.4, 5.6 Hz, 1H), 1.79-1.63 (m, 1H), 1.51-1.37 (m, 1H). LC/MS,m/z=429.2 [M+H]⁺ (Calc: 428.5);

(4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-7-(2-oxo-2-(piperidin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(TFA salt) (Compound 80): ¹H NMR δ_(H) (400 MHz, CD₃OD): 7.06 (d, J=8.4Hz, 1H), 6.79 (d, J=2.4 Hz, 1H), 6.69 (dd, J=8.4, 2.4 Hz, 1H), 3.57 (d,J=6.2 Hz, 1H), 3.55-3.33 (m, 6H), 3.26-3.13 (m, 2H), 3.09 (dd, J=12.7,4.3 Hz, 1H), 2.93 (s, 4H), 2.78 (dd, J=16.5, 6.8 Hz, 1H), 2.74-2.63 (m,1H), 2.61-2.47 (m, 1H), 2.08 (dd, J=13.8, 6.1 Hz, 1H), 1.91 (dd, J=16.5,5.9 Hz, 1H), 1.78-1.68 (m, 1H), −1.68-1.44 (m, 6H), 1.43-1.34 (m, 1H).LC/MS, m/z=413.4 [M+H]⁺ (Calc: 412.5);

(4bR,7R,8aS,9R)-3,8a-dihydroxy-7-(2-(4-hydroxypiperidin-1-yl)-2-oxoethyl)-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one(Compound 81): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.13 (br. s., 1H), 6.91(d, J=8.1 Hz, 1H), 6.68-6.57 (m, 1H), 6.55-6.47 (m, 1H), 4.87-4.72 (m,1H), 4.69 (t, J=4.6 Hz, 1H), 3.95-3.75 (m, 1H), 3.70-3.50 (m, 2H),3.44-3.35 (m, 1H), 3.14-3.00 (m, 2H), 3.00-2.70 (m, 3H), 2.70-2.54 (brs, 3H), 2.42-2.25 (m, 3H), 2.20-2.06 (m, 1H), 2.02-1.85 (m, 1H),1.85-1.56 (m, 4H), 1.52-1.40 (m, 1H), 1.36-1.09 (m, 3H), 1.02 (d, J=11.9Hz, 1H). LC/MS, m/z=429.2 [M+H]⁺ (Calc: 428.5);

2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-N-isobutylacetamide(Compound 82): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.14 (br. s., 1H), 7.67(t, J=5.8 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 6.62 (d, J=2.2 Hz, 1H),6.57-6.49 (m, 1H), 4.79 (br. s., 1H), 3.25-3.14 (m, 1H), 3.07 (d, J=18.3Hz, 1H), 2.93 (d, J=13.4 Hz, 1H), 2.84-2.73 (m, 3H), 2.65 (d, J=13.4 Hz,2H), 2.42-2.24 (m, 5H), 2.20-2.04 (m, 1H), 2.01-1.84 (m, 1H), 1.84-1.69(m, 1H), 1.61 (s, 2H), 1.47-1.33 (m, 1H), 1.10-0.93 (m, 1H), 0.81 (s,3H), 0.79 (s, 3H). LC/MS, m/z=401.4 [M+H]⁺ (Calc: 400.5);

N-benzyl-2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamide(TFA salt) (Compound 83): ¹H NMR δ_(H) (400 MHz, CD₃OD): 8.33 (br s,1H), 7.28 (d, J=5.7 Hz, 4H), 7.06 (d, J=8.4 Hz, 1H), 6.79 (d, J=2.2 Hz,1H), 6.69 (dd, J=8.4, 2.4 Hz, 1H), 4.24-4.42 (m, 2H), 3.56 (d, J=6.2 Hz,1H), 3.45-3.33 (m, 3H), 3.23-3.06 (m, 3H), 2.96-2.89 (m, 4H), 2.77-2.64(m, 1H), 2.61-2.47 (m, 2H), 2.05 (dd, J=13.6, 6.2 Hz, 1H), 1.90 (dd,J=15.3, 6.5 Hz, 1H), 1.78-1.65 (m, 1H), 1.48-1.33 (m, 1H). LC/MS,m/z=435.2 [M+H]⁺ (Calc: 434.53); and

N-(cyclopropylmethyl)-2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamide(TFA salt) (Compound 84): ¹H NMR δ_(H) (400 MHz, DMSO-d₆): 9.37 (s, 1H),9.24 (br s, 1H), 7.79 (t, J=5.5 Hz, 1H), 7.00 (d, J=8.1 Hz, 1H), 6.68(d, J=2.4 Hz, 1H), 6.64 (dd, J=8.4, 2.4 Hz, 1H), 6.34 (s, 1H), 3.56 (d,J=5.9 Hz, 1H), 3.33-3.21 (m, 2H), 3.09-2.94 (m, 3H), 2.92-2.85 (m, 2H),2.82 (d, J=5.1 Hz, 3H), 2.76 (d, J=13.6 Hz, 1H), 2.47-2.37 (m, 1H),2.36-2.23 (m, 2H), 1.98 (dd, J=13.6, 6.4 Hz, 1H), 1.63 (dd, J=15.0, 6.8Hz, 1H), 1.54-1.40 (m, 1H), 1.28 (d, J=13.2 Hz, 1H), 0.90-0.74 (m, 1H),0.43-0.30 (m, 2H), 0.17-0.04 (m, 2H). LC/MS, m/z=399.2 [M+H]⁺ (Calc:398.5).

In the foregoing Examples the following abbreviations are used:

Ac acetyl ACN acetonitrile AcOH acetic acid Ac₂O acetic anhydride aq.aqueous atm atmosphere(s) Bn benzyl Boc tert-butoxycarbonyl ° C. degreesCelcius conc. concentrated DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE1,2-dichloroethane DCM dichloromethane DIBAL diisobutylaluminum hydrideDIPEA diisopropylethylamine DMF dimethylformamide DMSO dimethylsulfoxideEt₂O diethyl ether EtOAc ethyl acetate EtOH ethanol h hour(s) HATU2-(7-aza-1H-benzotriazole-1-yl)- 1,1,3,3-tetramethyluroniumhexafluorophosphate HPLC high pressure liquid chromatography MeOHmethanol min minute(s) MPLC medium pressure liquid chromatography NaHMDSsodium hexamethyldisilazide Pd/C palladium on carbon Pd(Ph₃P)₄tetrakis(triphenylphosphine)palladium(0) psi pounds per square inch PTSAp-toluenesulfonic acid RT room temperature satd. saturated TBDPStert-butyldiphenylsilyl TFA trifluoroacetic acid THF tetrahydrofuran

The following tables provide results on the efficacy of binding andactivity response of exemplified Compounds of the Invention at the μ-and κ-opioid receptors. In TABLE 3, binding affinity of certainCompounds of the Invention to the μ- and μ-opioid receptors wasdetermined as described above. In TABLE 4, activity response of certainCompounds of the Invention to the μ- and κ-opioid receptors wasdetermined as described above for functional assays using HEK-293 cells.In TABLE 5, activity response of certain Compounds of the Invention tothe μ- and κ-opioid receptors was determined as described above usingU-2 OS cells.

TABLE 3 Binding Affinity Opioid Receptor K_(i) (nM) Compound [mean ±SEM] No. κ μ 1 407.78 ± 34.14 8 260.85 ± 97.28 9  0.97 ± 0.19 6.18 ±0.76 10 >20000 12 3410.66 ± 537.83 13 >20000 15 190.65 ± 45.81 16 >2000017 128.06 ± 18.10 18 15905.72 19 145.53 ± 29.67 24  249.2 ± 104.2 668.0± 118.5 46 394.2 ± 85.2 591.0 ± 80.3  48  65.3 ± 4.49 222.8 ± 32.5  49324.4 ± 48.0  1959 ± 638.1 72  82.9 ± 1.96 476.0 ± 117.8 73  0.32 ± 0.111.98 ± 0.44 74  0.33 ± 0.041 7.42 ± 2.25

TABLE 4 Activity Response μ κ EC₅₀ (nM) EC₅₀ (nM) Compound No. [mean ±SEM] E_(max) (%) [mean ± SEM] E_(max) (%) Opioid Receptor (HEK-293cells) 1 3397.92 ± 584.13 59.33 ± 3.38  5114.25 ± 1261.73 72.00 ± 3.21 8 702.68 ± 72.01 59.67 ± 8.69  4435.58 ± 678.77  66.67 ± 6.84  9 >200000−1.00 ± 0.00  17.30 ± 3.73  40.75 ± 1.93  10 14670.57 ± 1534.34 16.00 ±2.65  12 >200000 — 13 4604.07 ± 471.18 66.00 ± 2.65  15  43.75 ± 14.6536.25 ± 3.75  220.91 ± 59.35  36.00 ± 2.00  16  6770.22 ± 1369.30 28.67± 1.86  17 >200000 0.00 ± 0.58 >200000 — 18 2749.52 ± 220.89 50.00 ±1.53  19 49.72 ± 7.48 37.50 ± 3.93  201.13 ± 25.95  41.33 ± 2.85 42 >200000 5.50 43 >200000 0.00 48 463.0 ± 32.6 139.0 ± 3.21  362.3 ±36.6  70.3 ± 6.94 54  14.2 ± 3.39 25.0 ± 2.04 5.02 ± 0.14 34.3 ± 0.6764 >200000 1.00 4.30 ± 1.55 33.0 ± 1.73 72   212 ± 48.8 100.7 ± 5.55  1052 ± 192.8 69.3 ± 6.77 73  2.85 ± 0.60 53.2 ± 5.71 6.07 ± 1.92 61.0 ±8.62 74  2.31 ± 0.60 90.3 ± 3.84 3.52 ± 1.00 34.0 ± 5.86 82   2331 ±199.6 67.8 ± 4.01 83 456.5 ± 36.7 75.0 ± 5.51 84   1258 ± 301.1 57.7 ±2.73 Opioid Receptor (U-2 OS cells) 23   2102 ± 735.1 15.7 ± 3.71  5560± 480.7 90.0 ± 1.00 24  463.0 ± 120.9 43.2 ± 7.97 317.1 ± 21.1  102.0 ±5.86  25 578.2 ± 91.8 36.0 ± 3.51 876.5 ± 18.8  105.7 ± 3.28  26   7112± 632.8 31.0 ± 2.08  7213 ± 437.5 104.0 ± 2.52  27 >200000 8.00 ± 2.1224.7 ± 3.18 92.7 ± 3.18 28 >200000 2.50 27.1 ± 3.29 86.7 ± 2.4029 >200000 7.25 ± 1.89 14.6 ± 1.86 98.7 ± 5.21 30  9.61 ± 0.83 51.0 ±2.65 1.61 ± 0.12 97.7 ± 3.18 31  9.65 ± 0.22 73.7 ± 2.60 2.59 ± 0.1490.7 ± 6.57 32  18.6 ± 8.05 11.3 ± 0.88 17.5 ± 2.66 113.0 ± 3.61 33 >200000 2.50 36.1 ± 3.14 52.0 ± 4.93 34 >200000 6.33 ± 2.19 12.6 ±2.04 100.7 ± 3.33  35 >200000 2.00 13.6 ± 1.04 85.7 ± 2.40 36  12.7 ±2.92 20.3 ± 0.33 4.28 ± 0.60 99.0 ± 4.73 37 >200000 6.00 ± 1.53 42.1 ±7.56 71.3 ± 5.70 38  10.3 ± 1.72 40.3 ± 1.45 2.30 ± 0.25 95.3 ± 5.21 46408.7 ± 88.5 68.7 ± 4.10 1016 ± 110.1 109.3 ± 4.84  48  38.6 ± 2.85 98.0± 2.65 225.1 ± 20.1  118.7 ± 4.91  49  1282 ± 159.6 108.0 ± 5.57  50147.8 ± 10.4 101.7 ± 1.67   7896 ± 706.9 74.0 ± 5.29 54  1.81 ± 0.5726.3 ± 2.33 4.82 ± 0.71 88.2 ± 2.53 58  787.3 ± 242.1 43.7 ± 3.93 838.8± 9.90  96.0 ± 6.35 59  11549 ± 902.8 100.0 ± 4.62  >200000 59.0 ± 1.5360 14890 ± 1323  84.3 ± 0.67 61 466.1 ± 81.0 77.3 ± 2.03 963.2 ± 83.0 90.0 ± 10.0 62 >200000 27.5   3067 ± 233.4 62.7 ± 4.37 64 >200000 7.504.71 ± 0.12 87.3 ± 2.60 65 >200000 4.00 2.57 ± 0.24 101.0 ± 5.51 66 >200000 2.50 7.57 ± 1.14 101.7 ± 1.33  67 >200000 2.00 3.00 ± 0.12101.0 ± 1.73  68 >200000 3.00 20.5 ± 0.40 69.0 ± 3.21 69 >200000 2.009.52 ± 1.41 95.2 ± 1.89 70 >200000 3.50 4.01 ± 0.47 105.5 ± 3.80  71 6.76 ± 1.73 17.7 ± 0.88 5.60 ± 0.72 109.0 ± 5.45  72 269.7 ± 48.2 60.0± 6.00 302.8 ± 40.4  102.0 ± 2.52  73  0.84 ± 0.13 28.3 ± 4.06 1.92 ±0.28 100.7 ± 3.38  74  3.66 ± 0.82 46.0 ± 11.0 1.42 ± 0.15 91.3 ± 3.7675   1153 ± 102.8 95.0 ± 1.53 16592 ± 1193  66.7 ± 1.20 76 16697 ± 227261.7 ± 1.86 >200000 47.7 ± 2.19 77 17630 ± 3649 77.0 ± 2.08 >200000 49.0± 9.45 78 10398 ± 4813 36.7 ± 9.17 >200000 53.3 ± 1.45 79 11657 ± 362560.0 ± 10.2 >200000 51.0 ± 0.58 80 580.8 ± 22.1 74.0 ± 0.58  1198 ±114.1 43.0 ± 1.73 81   1005 ± 276.2 84.3 ± 3.84 6508 ± 1194 34.0 ± 2.65

The in vitro test results of TABLES 3-5 show that representativeCompounds of the Invention have binding affinity for opioid receptors,and that these compounds activate these receptors as partial to fullagonists. Compounds of the Invention are therefore expected to be usefulto treat Conditions, particularly pain, that are responsive to theactivation of one or more opioid receptors.

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents, patent applications, and publications cited herein arefully incorporated by reference herein in their entirety.

1-82. (canceled)
 83. A compound having the Formula I-A:

or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹ ishydrogen, OH, halo, cyano, carboxy, or aminocarbonyl; or alkyl, alkenyl,alkynyl, alkoxy, alkenyloxy, or alkynyloxy, any of which is optionallysubstituted with 1, 2, or 3 substituents, each independently selectedfrom the group consisting of hydroxy, halo, haloalkyl, amino,alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionallysubstituted with 1, 2, or 3 independently selected R^(11a) groups; or—O—PG, wherein PG is a hydroxyl protecting group; R² is: (a) hydrogen orcarboxamido; or (b) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl,(heterocyclo)alkyl, arylalkyl, heteroarylalkyl, alkylcarbonyl,alkoxycarbonyl, (arylalkoxy)carbonyl, or (heteroarylalkoxy)carbonyl, anyof which is optionally substituted with 1, 2, or 3 substituents, eachindependently selected from the group consisting of hydroxy, alkyl,halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy,alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl, wherein the aryl, heteroaryl, heterocyclo, cycloalkyl, andcycloalkenyl are optionally substituted with 1, 2, or 3 independentlyselected R^(11a) groups; R³ is hydrogen, OH, or halo; or alkoxy,alkylamino, or dialkylamino, any of which is optionally substituted with1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxyl, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl are optionally substitutedwith 1, 2, or 3 independently selected R^(11a) groups; R^(4a1) isselected from the group consisting of C₃-C₆ alkyl, arylalkyl,(cycloalkyl)alkyl, C₃-C₆ alkoxy, aralkyloxy, —N(H)COR^(4c),—CH₂C(═O)NR^(4d)R^(4e), and —N(H)SO₂R^(4f),

R^(4b1) is selected from the group consisting of hydrogen and R^(4a)-I;or R^(4a1) and R^(4b1) taken together form an alkenyl; R^(4c) is alkyl,cycloalkyl, heterocyclo, arylalkyl, or aryl, any of which is optionallysubstituted with 1, 2, or 3 substituents, each independently selectedfrom the group consisting of hydroxy, alkyl, halo, haloalkyl, amino,alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryland cycloalkyl are optionally substituted with 1, 2, or 3 independentlyselected R^(11a) groups; R^(4d) is hydrogen; or alkyl, cycloalkyl,arylalkyl, or aryl, any of which is optionally substituted with 1, 2, or3 substituents, each independently selected from the group consisting ofhydroxy, alkyl, halo, haloalkyl, amino, alkylamino, dialkylamino,carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo,cycloalkyl, and cycloalkenyl, wherein the aryl, heteroaryl, heterocyclo,cycloalkyl, and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R^(11a) groups; R^(4e) is hydrogen; or alkyl,optionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, alkyl, halo, haloalkyl,amino, alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl; or R^(4d) andR^(4e) taken together with the nitrogen atom to which they are attachedform a 4- to 8-membered heterocyclo, wherein the heterocyclo isoptionally substituted with 1 or 2 substituents, each independentlyselected from the group consisting of alkyl, hydroxy, halo, haloalkyl,amino, alkylamino, dialkylamino, alkoxy, aminocarbonyl, arylalkyl, andaryl, wherein the alkyl, arylalkyl, and aryl are optionally substitutedwith 1, 2, or 3 independently selected R^(11a) groups; R^(4f) is alkyl,cycloalkyl, arylalkyl, or aryl, any of which is optionally substitutedwith 1, 2, or 3 substituents, each independently selected from the groupconsisting of hydroxy, alkyl, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl,heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl andcycloalkyl are optionally substituted with 1, 2, or 3 independentlyselected R^(11a) groups; each R^(5a), R^(5b), R^(5c), R^(5d), R^(5e),and R^(5f) is independently selected from the group consisting ofhydrogen and alkyl; R⁶ is hydrogen or alkyl; R⁷ is hydrogen or alkyl;R^(8a) is hydrogen, or alkyl, cycloalkyl, cycloalkenyl, heterocyclo,aryl, heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl,(heterocyclo)alkyl, arylalkyl, or heteroarylalkyl, any of which isoptionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, alkyl, halo, haloalkyl,amino, alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionallysubstituted with 1, 2, or 3 independently selected R^(11a) groups;R^(8b) is hydrogen or alkyl, wherein the alkyl is optionally substitutedwith 1, 2, or 3 substituents, each independently selected from the groupconsisting of alkyl, hydroxy, halo, haloalkyl, amino, alkylamino,dialkylamino, carboxy, alkoxy, alkoxycarbonyl, and aminocarbonyl; orR^(8a) and R^(8b) taken together with the carbon atom to which they areattached form a 3- to 8-membered cycloalkyl; or R⁷ and R^(8a) takentogether with the atoms to which they are attached form a 4- to8-membered heterocyclo, wherein the heterocyclo is optionallysubstituted with 1 or 2 substituents, each independently selected fromthe group consisting of alkyl, hydroxy, halo, haloalkyl, amino,alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, andaminocarbonyl; R⁹ is hydrogen or alkyl; R¹⁰ is hydrogen, or alkyl,cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl,(cycloalkyl)alkyl, (cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl,or heteroarylalkyl, any of which is optionally substituted with 1, 2, or3 substituents, each independently selected from the group consisting ofhydroxy, alkyl, halo, haloalkyl, amino, alkylamino, dialkylamino,carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo,cycloalkyl, and cycloalkenyl, wherein the aryl, heteroaryl, heterocyclo,cycloalkyl, and cycloalkenyl are optionally substituted with 1, 2, or 3independently selected R^(11a) groups; each R^(11a) is independentlyselected from the group consisting of hydroxy, halo, alkyl, haloalkyl,cyano, nitro, amino, alkylamino, dialkylamino, carboxy, alkoxy, andalkoxycarbonyl; n is 1, 2, or 3; o is 1, 2, or 3; and p is 1, 2, or 3.84. The compound of claim 83 having the Formula IV-A:

or a pharmaceutically acceptable salt or solvate thereof.
 85. Thecompound of claim 83 having the Formula V-A:

or a pharmaceutically acceptable salt or solvate thereof.
 86. Thecompound of claim 83, or a pharmaceutically acceptable salt or solvatethereof, wherein R^(4a1) is selected from the group consisting of:


87. The compound of claim 83, or a pharmaceutically acceptable salt orsolvate thereof, wherein R^(4a1) is selected from the group consistingof C₃-C₆ alkyl, arylalkyl, (cycloalkyl)alkyl, C₃-C₆ alkoxy, aralkyloxy,—N(H)COR^(4c), —CH₂C(═O)NR^(4d)R^(4e), and —N(H)SO₂R^(4f).
 88. Thecompound of claim 87, or a pharmaceutically acceptable salt or solvatethereof, wherein: R¹ is OH or unsubstituted C₁₋₆ alkoxy; R² is alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl,heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (heterocyclo)alkyl,arylalkyl, heteroarylalkyl, alkylcarbonyl, alkoxycarbonyl,(arylalkoxy)carbonyl, or (heteroarylalkoxy)carbonyl, any of which isoptionally substituted with 1, 2, or 3 substituents, each independentlyselected from the group consisting of hydroxy, alkyl, halo, haloalkyl,amino, alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein the aryl,heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionallysubstituted with 1, 2, or 3 independently selected R¹¹ groups; and R³ ishydrogen or hydroxy.
 89. The compound of claim 88, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R^(4a1) is selected from thegroup consisting of C₃-C₆ alkyl, arylalkyl, and (cycloalkyl)alkyl. 90.The compound of claim 88, or a pharmaceutically acceptable salt orsolvate thereof, wherein R^(4a1) is selected from the group consistingof C₃-C₆ alkoxy and aralkyloxy.
 91. The compound of claim 88, or apharmaceutically acceptable salt or solvate thereof, wherein R^(4a1) isselected from the group consisting of N(H)COR^(4c),CH₂C(═O)NR^(4d)R^(4e), and —N(H)SO₂R^(4f).
 92. The compound of claim 83having the Formula XIV:

or a pharmaceutically acceptable salt or solvate thereof, wherein R ishydrogen, alkyl, or cycloalkyl.
 93. The compound of claim 83 having theFormula XV:

or a pharmaceutically acceptable salt or solvate thereof.
 94. Thecompound of claim 93, or a pharmaceutically acceptable salt or solvatethereof, wherein: R¹ is selected from the group consisting of OH andmethoxy; R² is selected from the group consisting of —CH₃ and—CH₂(cyclopropyl); and R³ is selected from the group consisting ofhydrogen and OH; and R^(4a1) is selected from the group consisting ofC₃-C₆ alkyl, (cycloalkyl)alkyl, C₃-C₆ alkoxy, aralkyloxy, —N(H)COR^(4c),—CH₂C(═O)NR^(4d)R^(4e), —N(H)SO₂R^(4f),


95. The compound of claim 94, or a pharmaceutically acceptable salt orsolvate thereof, wherein R^(4a1) is selected from the group consistingof C₃-C₆ alkyl, (cycloalkyl)alkyl, C₃-C₆ alkoxy, aralkyloxy,—N(H)COR^(4c), —CH₂C(═O)NR^(4d)R^(4e), and —N(H)SO₂R^(4f).
 96. Thecompound of claim 83 having the Formula XVI:

or a pharmaceutically acceptable salt or solvate thereof; wherein R¹ isselected from the group consisting of OH and methoxy; R² is selectedfrom the group consisting of —CH₃ and —CH₂(cyclopropyl); and R³ isselected from the group consisting of hydrogen and OH; and R^(4a1) isselected from the group consisting of C₃-C₆ alkyl, (cycloalkyl)alkyl,C₃-C₆ alkoxy, aralkyloxy, —N(H)COR^(4c), —CH₂C(═O)NR^(4d)R^(4e),—N(H)SO₂R^(4f),


97. The compound of claim 83 selected from the group consisting of:(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-7-isobutoxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7S,8aS,9R)-7-(benzyloxy)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)isobutyramide;N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)isobutyramide;N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamide;N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)propionamide;N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-4-methylpentanamide;N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-5-methylhexanamide;N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)pivalamide;N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-3-methylbutanamide;N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)cyclopropanecarboxamide;N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)cyclopentanecarboxamide;N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)benzamide;(S)—N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-2-methylbutanamide;N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)cyclohexanecarboxamide;N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)ethanesulfonamide;N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)benzenesulfonamide;(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-7-(2-hydroxyethyl)-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7S,8aS,9R)-7-(2-(benzyloxy)ethyl)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-7-(2-methoxyethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7 S,8aS,9R)-7-(2-(benzyloxy)ethyl)-8a-hydroxy-3-methoxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-hydroxyethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7S,8aS,9R)-3-(benzyloxy)-11-(cyclopropylmethyl)-8a-hydroxy-7-(2-hydroxyethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one; ethyl2-((4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetate;2-((4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)aceticacid; 2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)aceticacid;(4bR,8aS,9R,E)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-7-(3-methylbutylidene)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7 S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-isopentyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4 bR,7 S,8aS,9R)-7-(cyclopentylmethyl)-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-methylbutyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7S,8aS,9R)-7-butyl-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7 S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-neopentyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-isobutyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7S,8aS,9R)-7-(cyclohexylmethyl)-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7S,8aS,9R)-7-benzyl-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bS,7S,8aR,9R)-11-(cyclopropylmethyl)-7-isopropyl-3-methoxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bS,7S,8aR,9R)-11-(cyclopropylmethyl)-3-hydroxy-7-isopropyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bS,7R,8aR,9R)-11-(cyclopropylmethyl)-3-hydroxy-7-isopropyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetyl)-L-alanine;(4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-7-(2-oxo-2-(piperidin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-7-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7R,8aS,9R)-8a-hydroxy-7-(2-(4-hydroxypiperidin-1-yl)-2-oxoethyl)-3-methoxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7R,8aS,9R)-8a-hydroxy-3-methoxy-11-methyl-7-(2-morpholino-2-oxoethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-7-(2-oxo-2-(piperidin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7R,8aS,9R)-3,8a-dihydroxy-7-(2-(4-hydroxypiperidin-1-yl)-2-oxoethyl)-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-N-isobutylacetamide;N-benzyl-2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamide;N-(cyclopropylmethyl)-2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamide;2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-N-(2-hydroxyethyl)acetamide;2-((4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-N-(3-hydroxypropyl)acetamide;2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-N-(2-hydroxyethyl)acetamide;2-((4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-N-(3-hydroxypropyl)acetamide;(4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-7-(2-oxo-2-(piperazin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-7-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7R,8aS,9R)-7-(2-(4-benzylpiperazin-1-yl)-2-oxoethyl)-3,8a-dihydroxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7R,8aS,9R)-3,8a-dihydroxy-11-methyl-7-(2-oxo-2-(4-phenylpiperazin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-oxo-2-(piperazin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7R,8aS,9R)-7-(2-(4-benzylpiperazin-1-yl)-2-oxoethyl)-11-(cyclopropylmethyl)-3,8a-dihydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-7-(2-oxo-2-(4-phenylpiperazin-1-yl)ethyl)-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)acetamide;N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)propionamide;N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)isobutyramide;N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)pivalamide;N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-4-methylpentanamide;N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-5-methylhexanamide;N-((4bR,7S,8aS,9R)-3,8a-dihydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)cyclohexanecarboxamide;(4bS,7S,8aR,9R)-11-(cyclopropylmethyl)-3-hydroxy-7-isopentyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bS,7S,8aR,9R)-7-(cyclopentylmethyl)-11-(cyclopropylmethyl)-3-hydroxy-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bR,7S,8aS,9R)-3,8a-dihydroxy-7-isopentyl-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;(4bS,7S,8aR,9R)-7-(cyclopentylmethyl)-3-hydroxy-11-methyl-8,8a,9,10-tetrahydro-5H-9,4b-(epiminoethano)phenanthren-6(7H)-one;N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)methanesulfonamide;N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)piperidine-4-carboxamide;and N-((4bR,7S,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-7-yl)-2-(dimethylamino)acetamideor a pharmaceutically acceptable salt or solvate thereof.
 98. Apharmaceutical composition comprising a compound of claim 83, or apharmaceutically acceptable salt or solvate thereof, and one or morepharmaceutically acceptable carriers.
 99. A method of treating orpreventing pain, constipation, diarrhea, pruritis, an addictivedisorder, withdrawal from alcohol addiction or withdrawal from drugaddiction in a patient, comprising administering an effective amount ofa compound of claim 83, or a pharmaceutically acceptable salt or solvatethereof, to a patient in need of such treatment or prevention.
 100. Themethod of claim 99, wherein the method is for treating pain.
 101. Themethod of claim 100, wherein said pain is acute pain, chronic pain, orsurgical pain.
 102. A method of modulating one or more opioid receptorsin a patient, comprising administering to the patient an effectiveamount of a compound of claim 83, or a pharmaceutically acceptable saltor solvate thereof.
 103. The method of claim 102, wherein the μ- orκ-opioid receptor is modulated, or both the μ- and κ-opioid receptorsare modulated.